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  • 1.
    Barbu, Andreea
    et al.
    Uppsala University, Sweden; Uppsala University, Sweden.
    Jansson, Leif
    Uppsala University, Sweden.
    Sandberg, Monica
    Uppsala University, Sweden.
    Quach, My
    Uppsala University, Sweden.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Uppsala University, Sweden.
    The use of hydrogen gas clearance for blood flow measurements in single endogenous and transplanted pancreatic islets2015In: Microvascular Research, ISSN 0026-2862, E-ISSN 1095-9319, Vol. 97, p. 124-129Article in journal (Refereed)
    Abstract [en]

    The blood perfusion of pancreatic islets is regulated independently from that of the exocrine pancreas, and is of importance for multiple aspects of normal islet function, and probably also during impaired glucose tolerance. Single islet blood flow has been difficult to evaluate due to technical limitations. We therefore adapted a hydrogen gas washout technique using microelectrodes to allow such measurements. Platinum micro-electrodes monitored hydrogen gas clearance from individual endogenous and transplanted islets in the pancreas of male Lewis rats and in human and mouse islets implanted under the renal capsule of male athymic mice. Both in the rat endogenous pancreatic islets as well as in the intra-pancreatically transplanted islets, the vascular conductance and blood flow values displayed a highly heterogeneous distribution, varying by factors 6-10 within the same pancreas. The blood flow of human and mouse islet grafts transplanted in athymic mice was approximately 30% lower than that in the surrounding renal parenchyma. The present technique provides unique opportunities to study the islet vascular dysfunction seen after transplantation, but also allows for investigating the effects of genetic and environmental perturbations on islet blood flow at the single islet level in vivo. (C) 2014 The Authors. Published by Elsevier Inc.

  • 2.
    Carlström, Mattias
    et al.
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Brown, Russell
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Edlund, Jenny
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Sällström, Johan
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Larsson, Erik
    Uppsala universitet, Institutionen för genetik och patologi.
    Teerlink, Tom
    Palm, Fredrik
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Wåhlin, Nils
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Persson, A. Erik G.
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals2008In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 294, no 2, p. 362-370Article in journal (Refereed)
    Abstract [en]

    Hydronephrotic animals develop renal injury and hypertension, which is associated with an abnormal tubuloglomerular feedback (TGF). The TGF sensitivity is coupled to nitric oxide (NO) in the macula densa. The involvement of reduced NO availability in the development of hypertension in hydronephrosis was investigated. Hydronephrosis was induced by ureteral obstruction in young rats. Blood pressure and renal excretion were measured in adulthood, under different sodium conditions, and before and after chronic administration of either N-G- nitro-L-arginine methyl ester (L-NAME) or L-arginine. Blood samples for ADMA, SDMA, and L-arginine analysis were taken and the renal tissue was used for histology and determination of NO synthase (NOS) proteins. TGF characteristics were determined by stop-flow pressure technique before and after administration of 7-nitroindazole (7-NI) or L-arginine. Hydronephrotic animals developed salt-sensitive hypertension, which was associated with pressure natriuresis and diuresis. The blood pressure response to L-NAME was attenuated and L-arginine supplementation decreased blood pressure in hydronephrotic animals, but not in the controls. Under control conditions, reactivity and sensitivity of the TGF response were greater in the hydronephrotic group. 7-NI administration increased TGF reactivity and sensitivity in control animals, whereas, in hydronephrotic animals, neuronal NOS (nNOS) inhibition had no effect. L-Arginine attenuated TGF response more in hydronephrotic kidneys than in controls. The hydronephrotic animals displayed various degrees of histopathological changes. ADMA and SDMA levels were higher and the renal expressions of nNOS and endothelial NOS proteins were lower in animals with hydronephrosis. Reduced NO availability in the diseased kidney in hydronephrosis, and subsequent resetting of the TGF mechanism, plays an important role in the development of hypertension.

  • 3.
    Davids, Mariska
    et al.
    Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands, Institute for Cardiovascular Research (ICaR-VU), Amsterdam, The Netherlands, .
    Swieringa, Eliane
    Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Smith, Desirée E C
    Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
    Smulders, Yvo M
    Institute for Cardiovascular Research (ICaR-VU), Amsterdam, The Netherlands, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands.
    Scheffer, Peter G
    Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands, Institute for Cardiovascular Research (ICaR-VU), Amsterdam, The Netherlands.
    Blom, Henk J
    Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands, Institute for Cardiovascular Research (ICaR-VU), Amsterdam, The Netherlands.
    Teerlink, Tom
    Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands, Institute for Cardiovascular Research (ICaR-VU), Amsterdam, The Netherlands.
    Simultaneous determination of asymmetric and symmetric dimethylarginine, l-monomethylarginine, l-arginine, and l-homoarginine in biological samples using stable isotope dilution liquid chromatography tandem mass spectrometry2012In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 900, p. 38-47Article in journal (Refereed)
    Abstract [en]

    Production of the endogenous vasodilator nitric oxide (NO) from l-arginine by NO synthase is modulated by l-homoarginine, l-monomethylargine (MMA), asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). Here we report on a stable isotope dilution liquid chromatography tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of these metabolites in plasma, cells and tissues. After addition of the internal standards (D(7)-ADMA, D(4)-l-homoarginine and (13)C(6)-l-arginine), analytes were extracted from the samples using Waters Oasis MCX solid phase extraction cartridges. Butylated analytes were separated isocratically on a Waters XTerra MS C18 column (3.5μm, 3.9mm×100mm) using 600mg/L ammonium formate in water - acetonitrile (95.5:4.5, v/v) containing 0.1vol% formic acid, and subsequently measured on an AB Sciex API 3000 triple quadrupole mass spectrometer. Multiple reaction monitoring in positive mode was used for analyte quantification. Validation was performed in plasma. Calibration lines were linear (r(2)≥0.9979) and lower limits of quantification in plasma were 0.4nM for ADMA and SDMA and 0.8nM for the other analytes. Accuracy (% bias) was <3% except for MMA (<7%), intra-assay precision (expressed as CV) was <3.5%, inter-assay precision <9.6%, and recovery 92.9-103.2% for all analytes. The method showed good correlation (r(2)≥0.9125) with our previously validated HPLC-fluorescence method for measurement in plasma, and was implemented with good performance for measurement of tissue samples. Application of the method revealed the remarkably fast (i.e. within 60min) appearance in plasma of stable isotope-labeled ADMA, SDMA, and MMA during infusion of D(3)-methyl-1-(13)C-methionine in healthy volunteers.

  • 4.
    Eckerbom, Per
    et al.
    Uppsala universitet, Enheten för radiologi.
    Hansell, Peter
    Uppsala universitet, Integrativ Fysiologi.
    Bjerner, Tomas
    Uppsala universitet, Enheten för radiologi.
    Palm, Fredrik
    Uppsala universitet, Integrativ Fysiologi.
    Weis, Jan
    Uppsala universitet, Enheten för radiologi.
    Liss, Per
    Uppsala universitet, Enheten för radiologi.
    Intravoxel Incoherent Motion MR Imaging of the Kidney: Pilot Study2013In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 765, p. 55-58Article in journal (Refereed)
    Abstract [en]

    MR examinations (Achieva 3 T, Philips, Best, The Netherlands) were performed at five different occasions in a healthy volunteer (male 60 years) and in one renal cancer patient (male 78 years) with normal renal function (creatinine 88 μmol/L). Intravoxel incoherent motion (IVIM) coefficients D + D* were measured using respiratory-triggered diffusion-weighted spin-echo echo-planar imaging. Perfusion data of the patient were acquired using a saturation-recovery gradient-echo sequence and with the bolus of Gd-BOPTA (Multihance). D + D* were computed by monoexponential fitting of MR signal intensity attenuation versus b for b = 0, 50, 100, 150 s/mm2. Perfusion parameters were evaluated with “NordicICE” software. The map of D + D* was compared qualitatively with the perfusion map computed from the Gd scan. D + D* values of the cortex and medulla were in the range 2.3–2.7 and 1.1–1.6 × 10-3 mm2/s, respectively. In conclusion, in this pilot study a good qualitative relation between IVIM variables D + D* and renal perfusion has been found.

  • 5.
    Edlund, Jenny
    et al.
    Uppsala universitet, Integrativ Fysiologi.
    Fasching, Angelica
    Uppsala universitet, Integrativ Fysiologi.
    Liss, Per
    Uppsala universitet, Enheten för radiologi.
    Hansell, Peter
    Uppsala universitet, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Integrativ Fysiologi.
    The roles of NADPH-oxidase and nNOS for the increased oxidative stress and the oxygen consumption in the diabetic kidney2010In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 26, no 5, p. 349-356Article in journal (Refereed)
    Abstract [en]

    Background

    Sustained hyperglycaemia induces increased renal oxygen consumption resulting in reduced oxygen availability in the diabetic kidney. We investigated the roles of the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase and the neuronal nitric oxide synthase (nNOS) for the increased oxygen consumption in streptozotocin-diabetic rats.

    Methods

    Oxygen consumption was measured in isolated proximal tubular cells (PTC) from streptozotocin-induced diabetic rats (n = 7-9 per group) with and without chronic treatment with apocynin, a NADPH-oxidase inhibitor, or S-methyl-L-thiocitrulline (SMTC), a selective nNOS inhibitor, or a combination of the two and the results were compared to normoglycaemic controls (n = 10). Oxidative stress was estimated from thiobarbituric acid reactive substances and protein expression measured by Western blot.

    Results

    Proximal tubular cells from untreated diabetic rats had increased oxygen consumption compared to controls (40.6 +/- 7.9 versus 10.9 +/- 2.0 nmol/mg protein/min). All treatments reduced the diabetes-induced increase in oxygen consumption (apocynin 10.5 +/- 1.7, SMTC 19.7 +/- 3.0 and apocynin +/- SMTC 21.6 +/- 3.6 nmol/mg protein/min). Neither apocynin nor SMTC had any effect on the oxygen consumption in cells pre-incubated with ouabain, an inhibitor of active electrolyte transport. Oxidative stress was elevated in the diabetic kidney and inhibited by all treatments. The increased oxygen consumption by diabetic proximal tubular cells correlated with increased protein expressions of p47phox and nNOS and the treatments prevented these increases.

    Conclusions

    Diabetes induces oxidative stress, which increases oxygen consumption in proximal tubular cells. Inhibition of either NADPH-oxidase or nNOS prevented the increased oxygen consumption. The effect of blocking both these enzymes was less than additive suggesting overlapping pathways which warrant further studies.

  • 6.
    Edlund, Jenny
    et al.
    Uppsala universitet, Enheten för radiologi.
    Hansell, Peter
    Uppsala universitet, Integrativ Fysiologi.
    Fasching, Angelica
    Uppsala universitet, Integrativ Fysiologi.
    Liss, Per
    Uppsala universitet, Integrativ Fysiologi.
    Weis, Jan
    Uppsala universitet, Enheten för radiologi.
    Glickson, Jerry D.
    Palm, Fredrik
    Uppsala universitet, Integrativ Fysiologi.
    Reduced oxygenation in diabetic rat kidneys measured by T2* weighted magnetic resonance micro-imaging2009In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 645, p. 199-204Article in journal (Refereed)
    Abstract [en]

    By applying invasive techniques for direct measurements of oxygen tension, we have reported decreased kidney oxygenation in experimental diabetes in rats. However, the non-invasive MRI technique utilizing the BOLD effect provides several advantages with the possibility to perform repetitive measurements in the same animals and in human subjects. In this study, we applied a modified single gradient echo micro-imaging sequence to detect the BOLD effect in kidneys of diabetic rats and compared the results to normoglycemic controls. All measurements were performed on inactin-anaesthetized adult male Wistar Furth rats. Diabetes was induced by streptozotocin (45 mg/kg) 14 days prior to MRI-analysis. Sixteen T2*-weighted image records (B0=1.5 T) were performed using radiofrequency spoiled gradient echo sequence with 2.6 ms step increments of TE (TE1=12 ms), while TR (75 ms) and bandwidth per pixel (71.4 Hz) were kept constant. T2* maps were computed by mono-exponential fitting of the pixel intensities. Relaxation rates R2* (1/T2*) in cortex and outer stripe of the outer medulla were similar in both groups (cortex for controls 22.3 +/- 0.4 vs. diabetics 23.1 +/- 1.8 Hz and outer stripe of outer medulla for controls 24.9 +/- 0.4 vs. diabetics 26.4 +/- 1.8 Hz; n=4 in both groups), whereas R2* was increased in the inner stripe of the outer medulla in diabetic rats (diabetics 26.1 +/- 2.4 vs. controls 18.8 +/- 1.4 Hz; n=4, P<0.05). This study demonstrates that experimental diabetes in rats induces decreased oxygenation of the renal outer medulla. Furthermore, the proposed T2*-weighted MR micro-imaging technique is suitable for detection of regional changes in kidney oxygenation in experimental animal models.

  • 7.
    Franzén, Stephanie
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Fasching, Angelica
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Intrarenal activation of endothelin type B receptors improve intrarenal oxygenation in type 1 diabetic ratsManuscript (preprint) (Other academic)
  • 8.
    Franzén, Stephanie
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Friederich-Persson, Malou
    Uppsala University, Sweden .
    Fasching, Angelica
    Uppsala University, Sweden .
    Hansell, Peter
    Uppsala University, Sweden .
    Nangaku, Masaomi
    University of Tokyo, Japan .
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Differences in susceptibility to develop parameters of diabetic nephropathy in four mouse strains with type 1 diabetes2014In: AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, ISSN 1931-857X, Vol. 306, no 10, p. F1171-F1178Article in journal (Refereed)
    Abstract [en]

    One-third of diabetes mellitus patients develop diabetic nephropathy, and with underlying mechanisms unknown it is imperative that diabetic animal models resemble human disease. The present study investigated the susceptibility to develop diabetic nephropathy in four commonly used and commercially available mouse strains with type 1 diabetes to determine the suitability of each strain. Type 1 diabetes was induced in C57Bl/6, NMRI, BALB/c, and 129Sv mice by alloxan, and conscious glomerular filtration rate, proteinuria, and oxidative stress levels were measured in control and diabetic animals at baseline and after 5 and 10 wk. Histological alterations were analyzed using periodic acid-Schiff staining. Diabetic C57Bl/6 displayed increased glomerular filtration rate, i.e., hyperfiltration, whereas all other parameters remained unchanged. Diabetic NMRI developed the most pronounced hyperfiltration as well as increased oxidative stress and proteinuria but without glomerular damage. Diabetic BALB/c did not develop hyperfiltration but presented with pronounced proteinuria, increased oxidative stress, and glomerular damage. Diabetic 129Sv displayed proteinuria and increased oxidative stress without glomerular hyperfiltration or damage. However, all strains displayed intras-train correlation between oxidative stress and proteinuria. In conclusion, diabetic C57Bl/6 and NMRI both developed glomerular hyperfiltration but neither presented with histological damage, although NMRI developed low-degree proteinuria. Thus these strains may be suitable when investigating the mechanism causing hyperfiltration. Neither BALB/c nor 129Sv developed hyperfiltration although both developed pronounced proteinuria. However, only BALB/c developed detectable histological damage. Thus BALB/c may be suitable when studying the roles of proteinuria and histological alterations for the progression of diabetic nephropathy.

  • 9.
    Franzén, Stephanie
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Uppsala University, Sweden.
    Endothelin type A receptor inhibition normalises intrarenal hypoxia in rats used as a model of type 1 diabetes by improving oxygen delivery2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no 10, p. 2435-2442Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis Intrarenal tissue hypoxia, secondary to increased oxygen consumption, has been suggested as a unifying mechanism for the development of diabetic nephropathy. Increased endothelin-1 signalling via the endothelin type A receptor (ETA-R) has been shown to contribute to the development of chronic kidney disease, but its role in kidney oxygen homeostasis is presently unknown. Methods The effects of acute ETA-R inhibition (8 nmol/l BQ-123 for 30-40 min directly into the left renal artery) on kidney function and oxygen metabolism were investigated in normoglycaemic control and insulinopenic male Sprague Dawley rats (55 mg/kg streptozotocin intravenously 2 weeks before the main experiment) used as a model of type 1 diabetes. Results Local inhibition of ETA-R in the left kidney did not affect BP in either the control or the diabetic rats. As previously reported, diabetic rats displayed increased kidney oxygen consumption resulting in tissue hypoxia in both the kidney cortex and medulla. The inhibition of ETA-Rs restored normal kidney tissue oxygen availability in the diabetic kidney by increasing renal blood flow, but did not affect oxygen consumption. Furthermore, ETA-R inhibition reduced the diabetes-induced glomerular hyperfiltration and increased the urinary sodium excretion. Kidney function in normoglycaemic control rats was largely unaffected by BQ-123 treatment, although it also increased renal blood flow and urinary sodium excretion in these animals. Conclusions/interpretation Acutely reduced intrarenal ETA-R signalling results in significantly improved oxygen availability in the diabetic kidney secondary to elevated renal perfusion. Thus, the beneficial effects of ETA-R inhibition on kidney function in diabetes may be due to improved intrarenal oxygen homeostasis.

  • 10.
    Franzén, Stephanie
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences.
    Pihl, Liselotte
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Khan, Nadeem
    Gustafsson, Håkan
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Norrköping/Finspång. Linköping University, Faculty of Medicine and Health Sciences.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences.
    Pronounced kidney hypoxia precedes albuminuria in type 1 diabetic mice2016In: American Journal of Physiology, ISSN 0002-9513, E-ISSN 2163-5773, Vol. 310, no 9, p. F807-F809Article in journal (Refereed)
    Abstract [en]

    Intrarenal tissue hypoxia has been proposed as a unifying mechanism for the development of chronic kidney disease, including diabetic nephropathy. However, hypoxia has to be present before the onset of kidney disease in order to be the causal mechanism. In order to establish if hypoxia precedes the onset of diabetic nephropathy, we implemented a minimally invasive electron paramagnetic resonance oximetry technique using implanted oxygen sensing probes for repetitive measurements of in vivo kidney tissue oxygen tensions in mice. Kidney cortex oxygen tensions were measured before and up to 15 days after the induction of insulinopenic diabetes in male mice and compared to normoglycemic controls. On day 16, urinary albumin excretions and conscious glomerular filtration rates were determined in order to define the temporal relationship between intrarenal hypoxia and disease development. Diabetic mice developed pronounced intrarenal hypoxia three days after the induction of diabetes, which persisted throughout the study period. On day 16, diabetic mice had glomerular hyperfiltration, but normal urinary albumin excretion. In conclusion, intrarenal tissue hypoxia in diabetes precedes albuminuria thereby being a plausible cause for the onset and progression of diabetic nephropathy.

  • 11.
    Franzén, Stephanie
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Pihl, Liselotte
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Khan, Nadeem
    Geisel School Med, NH USA.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Uppsala University, Uppsala, Sweden .
    Gustafsson, Håkan
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Biomedical Engineering.
    Repetitive Measurements of Intrarenal Oxygenation In Vivo Using L Band Electron Paramagnetic Resonance2014In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 812, p. 135-141Article in journal (Refereed)
    Abstract [en]

    Intrarenal oxygenation is heterogeneous with oxygen levels normally being highest in the superficial cortex and lowest in the inner medulla. Reduced intrarenal oxygenation has been implied in the pathology of several kidney diseases. However, there is currently no method available to repetitively monitor regional renal oxygenation using minimally invasive procedures. We therefore evaluated implantable lithium phthalocyanine (LiPc) probes, which display a close correlation between EPR line width and oxygen availability. LiPc probes were implanted in the kidney cortex and medulla in the same mouse and sEPR spectra were acquired using a L band scanner during inhalation of air (21 % oxygen) or a mixture of air and nitrogen (10 % oxygen). In order to separate the signals from the two probes, a 1 G/cm gradient was applied and the signals were derived from 40 consecutive sweeps. Peak-to-peak comparison of the EPR line was used to convert the signal to an approximate oxygen tension in MATLAB. Kidney cortex as well as medullary oxygenation was stable over the 45 day period (cortex 56 +/- 7 mmHg and medulla 43 +/- 6 mmHg). However, 10 % oxygen inhalation significantly reduced oxygenation in both cortex (56 +/- 6 to 34 +/- 2 mmHg n = 15 p less than 0.05) and medulla (42 +/- 5 to 29 +/- 3 mmHg n = 7 p less than 0.05). In conclusion, L band EPR using LiPc probes implanted in discrete intrarenal structures can be used to repetitively monitor regional renal oxygenation. This minimally invasive method is especially well suited for conditions of reduced intrarenal oxygenation since this increases the signal intensity which facilitates the quantification of the EPR signal to absolute oxygenation values.

  • 12.
    Friederich, Malou
    et al.
    Uppsala universitet, Integrativ Fysiologi.
    Fasching, Angelica
    Uppsala universitet, Integrativ Fysiologi.
    Hansell, Peter
    Uppsala universitet, Integrativ Fysiologi.
    Nordquist, Lina
    Uppsala universitet, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Integrativ Fysiologi.
    Diabetes-induced up-regulation of uncoupling protein-2 results in increased mitochondrial uncoupling in kidney proximal tubular cells2008In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1777, no 7-8, p. 935-940Article in journal (Refereed)
    Abstract [en]

    We have previously reported increased O(2) consumption unrelated to active transport by tubular cells and up-regulated mitochondrial uncoupling protein (UCP)-2 expressions in diabetic kidneys. It is presently unknown if the increased UCP-2 levels in the diabetic kidney results in mitochondrial uncoupling and increased O(2) consumption, which we therefore investigated in this study. The presence of UCP-2 in proximal tubular cells was confirmed by immunohistochemistry and found to be increased (western blot) in homogenized tissue and isolated mitochondria from kidney cortex of diabetic rats. Isolated proximal tubular cells had increased total and ouabain-insensitive O(2) consumption compared to controls. Isolated mitochondria from diabetic animals displayed increased glutamate-stimulated O(2) consumption (in the absence of ADP and during inhibition of the ATP-synthase by oligomycin) compared to controls. Guanosine diphosphate, an UCP inhibitor, and bovine serum albumin which removes fatty acids that are essential for UCP-2 uncoupling activity, independently prevented the increased glutamate-stimulated O(2) consumption in mitochondria from diabetic animals. In conclusion, diabetic rats have increased mitochondrial UCP-2 expression in renal proximal tubular cells, which results in mitochondrial uncoupling and increased O(2) consumption. This mechanism may be protective against diabetes-induced oxidative stress, but will increase O(2) usage. The subsequently reduced O(2) availability may contribute to diabetes-induced progressive kidney damage.

  • 13.
    Friederich, Malou
    et al.
    Uppsala universitet, Integrativ Fysiologi.
    Hansell, Peter
    Uppsala universitet, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Integrativ Fysiologi.
    Diabetes, oxidative stress, nitric oxide and mitochondria function2009In: Current diabetes reviews, ISSN 1875-6417, Vol. 5, no 2, p. 120-144Article in journal (Refereed)
    Abstract [en]

    The role of altered mitochondria function has recently emerged as an important mechanism for the development of diabetic complications. Altered mitochondria function has also been implicated in the ageing process, defective insulin secretion, hypertension, arteriosclerosis, ischemia-reperfusion injury and apoptosis. Normally, the mitochondria are associated with ATP production using primarily pyruvate as the substrate, but recent reports indicate that tissue specific preferences exist. Also, the mitochondria are a substantial source of superoxide production, preferentially during states of elevated intracellular glucose concentrations. The mitochondria function is regulated by several factors including nitric oxide, oxidative stress, mammalian target of rapamycin, ADP and P(i) availability, which result in a complex regulation of ATP production and oxygen consumption, but also superoxide generation. These factors seem to be tissue specific, which warrants a more diverse mechanistic model applying to that specific tissue or cell type. This review presents the basic functions of the mitochondria and focuses on the complex interplay between oxidative stress, nitric oxide and uncoupling proteins in regulating mitochondria function with special focus on diabetes-induced alterations occurring on the mitochondria level.

  • 14.
    Friederich, Malou
    et al.
    Uppsala universitet, Integrativ Fysiologi.
    Nordquist, Lina
    Uppsala universitet, Integrativ Fysiologi.
    Olerud, Johan
    Uppsala universitet, Neuroanatomi.
    Johansson, Magnus
    Hansell, Peter
    Uppsala universitet, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Integrativ Fysiologi.
    Identification and distribution of uncoupling protein isoforms in the normal and diabetic rat kidney2009In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 645, p. 205-212Article in journal (Refereed)
    Abstract [en]

    Uncoupling protein (UCP)-2 and -3 are ubiquitously expressed throughout the body but there is currently no information regarding the expression and distribution of the different UCP isoforms in the kidney. Due to the known cross-reactivity of the antibodies presently available for detection of UCP-2 and -3 proteins, we measured the mRNA expression of UCP-1, -2 and -3 in the rat kidney in order to detect the kidney-specific UCP isoforms. Thereafter, we determined the intrarenal distribution of the detected UCP isoforms using immunohistochemistry. Thereafter, we compared the protein levels in control and streptozotocin-induced diabetic rats using Western blot. Expressions of the UCP isoforms were also performed in brown adipose tissue and heart as positive controls for UCP-1 and 3, respectively. UCP-2 mRNA was the only isoform detected in the kidney. UCP-2 protein expression in the kidney cortex was localized to proximal tubular cells, but not glomerulus or distal nephron. In the medulla, UCP-2 was localized to cells of the medullary thick ascending loop of Henle, but not to the vasculature or parts of the nephron located in the inner medulla. Western blot showed that diabetic kidneys have about 2.5-fold higher UCP-2 levels compared to controls. In conclusion, UCP-2 is the only isoform detectable in the kidney and UCP-2 protein can be detected in proximal tubular cells and cells of the medullary thick ascending loop of Henle. Furthermore, diabetic rats have increased UCP-2 levels compared to controls, but the mechanisms underlying this increase and its consequences warrants further studies.

  • 15. Friederich, Malou
    et al.
    Olerud, Johan
    Fasching, Angelica
    Liss, Per
    Uppsala universitet, Enheten för radiologi.
    Hansell, Peter
    Palm, Fredrik
    Uncoupling protein-2 in diabetic kidneys: increased protein expression correlates to increased non-transport related oxygen consumption2008In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 614, p. 37-43Article in journal (Refereed)
    Abstract [en]

    Diabetic patients have an elevated risk to develop renal dysfunction and it has been postulated that altered energy metabolism is involved. We have previously shown that diabetic rats have markedly decreased oxygen availability in the kidney, resulting from increased oxygen consumption. A substantial part of the increased oxygen consumption is unrelated to tubular transport, suggesting decreased mitochondrial efficiency. In this study, we investigated the protein expression of mitochondrial uncoupling protein (UCP)-2 in kidney tissue from control and streptozotocin (STZ)-induced diabetic rats. Protein levels of UCP-2 were measured in adult male control and STZ-diabetic Wistar Furth as well as Sprague Dawley rats in both the kidney cortex and medulla by Western blot technique. Two weeks of hyperglycemia resulted in increased protein levels of UCP-2 in kidneys from both Wistar Furth and Sprague Dawley rats. Both cortical and medullary UCP-2 levels were elevated 2-3 fold above control levels. We conclude that sustained STZ-induced hyperglycemia increases the kidney levels of mitochondrial UCP-2, which could explain the previously reported increase in non-transport related oxygen consumption in diabetic kidneys. The elevated UCP-2 levels may represent an effort to reduce the increased production of superoxide radicals which is evident during diabetes.

  • 16.
    Friederich-Persson, Malou
    et al.
    Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
    Aslam, Shakil
    Division of Nephrology and Hypertension, Department of Medicine, Kidney and Vascular Research Centre, Georgetown University Medical Center, Washington, D.C., United States of America.
    Nordquist, Lina
    Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
    Welch, William J
    Division of Nephrology and Hypertension, Department of Medicine, Kidney and Vascular Research Centre, Georgetown University Medical Center, Washington, D.C., United States of America.
    Wilcox, Christopher S
    Division of Nephrology and Hypertension, Department of Medicine, Kidney and Vascular Research Centre, Georgetown University Medical Center, Washington, D.C., United States of America.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Acute Knockdown of Uncoupling Protein-2 Increases Uncoupling via the Adenine Nucleotide Transporter and Decreases Oxidative Stress in Diabetic Kidneys2012In: PloS one, ISSN 1932-6203, Vol. 7, no 7, p. e39635-Article in journal (Refereed)
    Abstract [en]

    Increased O(2) metabolism resulting in chronic hypoxia is common in models of endstage renal disease. Mitochondrial uncoupling increases O(2) consumption but the ensuing reduction in mitochondrial membrane potential may limit excessive oxidative stress. The present study addressed the hypothesis that mitochondrial uncoupling regulates mitochondria function and oxidative stress in the diabetic kidney. Isolated mitochondria from kidney cortex of control and streptozotocin-induced diabetic rats were studied before and after siRNA knockdown of uncoupling protein-2 (UCP-2). Diabetes resulted in increased UCP-2 protein expression and UCP-2-mediated uncoupling, but normal mitochondria membrane potential. This uncoupling was inhibited by GDP, which also increased the membrane potential. siRNA reduced UCP-2 protein expression in controls and diabetics (-30-50%), but paradoxically further increased uncoupling and markedly reduced the membrane potential. This siRNA mediated uncoupling was unaffected by GDP but was blocked by ADP and carboxyatractylate (CAT). Mitochondria membrane potential after UCP-2 siRNA was unaffected by GDP but increased by CAT. This demonstrated that further increased mitochondria uncoupling after siRNA towards UCP-2 is mediated through the adenine nucleotide transporter (ANT). The increased oxidative stress in the diabetic kidney, manifested as increased thiobarbituric acids, was reduced by knocking down UCP-2 whereas whole-body oxidative stress, manifested as increased circulating malondialdehyde, remained unaffected. All parameters investigated were unaffected by scrambled siRNA. In conclusion, mitochondrial uncoupling via UCP-2 regulates mitochondria membrane potential in diabetes. However, blockade of the diabetes-induced upregulation of UCP- 2 results in excessive uncoupling and reduced oxidative stress in the kidney via activation of ANT.

  • 17.
    Friederich-Persson, Malou
    et al.
    Department of Medical Cell Biology, Div. Integrative Physiology, Uppsala University, Sweden.
    Persson, Patrik
    Department of Medical Cell Biology, Div. Integrative Physiology, Uppsala University, Sweden.
    Fasching, Angelica
    Department of Medical Cell Biology, Div. Integrative Physiology, Uppsala University, Sweden.
    Hansell, Peter
    Department of Medical Cell Biology, Div. Integrative Physiology, Uppsala University, Sweden.
    Nordquist, Lina
    Department of Medical Cell Biology, Div. Integrative Physiology, Uppsala University, Sweden.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Medical Cell Biology, Div. Integrative Physiology, Uppsala University, Biomedical Center.
    Increased kidney metabolism as a pathway to kidney tissue hypoxia and damage: effects of triiodothyronine and dinitrophenol in normoglycemic rats.2013In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 789, p. 9-14Article in journal (Refereed)
    Abstract [en]

    Intrarenal tissue hypoxia is an acknowledged common pathway to end-stage renal disease in clinically common conditions associated with development of chronic kidney disease, such as diabetes and hypertension. In diabetic kidneys, increased oxygen metabolism mediated by mitochondrial uncoupling results in decreased kidney oxygen tension (PO2) and contributes to the development of diabetic nephropathy. The present study investigated whether increased intrarenal oxygen metabolism per se can cause intrarenal tissue hypoxia and kidney damage, independently of confounding factors such as hyperglycemia and oxidative stress. Male Sprague-Dawley rats were untreated or treated with either triiodothyronine (T3, 10 g/kg bw/day, subcutaneously for 10 days) or the mitochondria uncoupler dinitrophenol (DNP, 30 mg/kg bw/day, oral gavage for 14 days), after which in vivo kidney function was evaluated in terms of glomerular filtration rate (GFR, inulin clearance), renal blood flow (RBF, Transonic, PAH clearance), cortical PO2 (Clark-type electrodes), kidney oxygen consumption (QO2), and proteinuria. Administration of both T3 and DNP increased kidney QO2 and decreased PO2 which resulted in proteinuria. However, GFR and RBF were unaltered by either treatment. The present study demonstrates that increased kidney metabolism per se can cause intrarenal tissue hypoxia which results in proteinuria. Increased kidney QO2 and concomitantly reduced PO2 may therefore be a mechanism for the development of chronic kidney disease and progression to end-stage renal disease.

  • 18.
    Friederich-Persson, Malou
    et al.
    Uppsala University, Sweden .
    Thorn, Erik
    Gothenburg University, Sweden .
    Hansell, Peter
    Uppsala University, Sweden .
    Nangaku, Masaomi
    University of Tokyo, Japan .
    Levin, Max
    Gothenburg University, Sweden .
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Kidney Hypoxia, Attributable to Increased Oxygen Consumption, Induces Nephropathy Independently of Hyperglycemia and Oxidative Stress2013In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 62, no 5, p. 914-919Article in journal (Refereed)
    Abstract [en]

    Diabetic nephropathy is strongly associated with both increased oxidative stress and kidney tissue hypoxia. The increased oxidative stress causes increased kidney oxygen consumption resulting in kidney tissue hypoxia. To date, it has been difficult to determine the role of kidney hypoxia, per se, for the development of nephropathy. We tested the hypothesis that kidney hypoxia, without confounding factors such as hyperglycemia or elevated oxidative stress, results in nephropathy. To induce kidney hypoxia, dinitrophenol (30 mg per day per kg bodyweight by gavage), a mitochondrial uncoupler that increases oxygen consumption and causes kidney hypoxia, was administered for 30 consecutive days to rats. Thereafter, glomerular filtration rate, renal blood flow, kidney oxygen consumption, kidney oxygen tension, kidney concentrations of glucose and glycogen, markers of oxidative stress, urinary protein excretion, and histological findings were determined and compared with vehicle-treated controls. Dinitrophenol did not affect arterial blood pressure, renal blood flow, glomerular filtration rate, blood glucose, or markers of oxidative stress but increased kidney oxygen consumption, and reduced cortical and medullary concentrations of glucose and glycogen, and resulted in intrarenal tissue hypoxia. Furthermore, dinitrophenol treatment increased urinary protein excretion, kidney vimentin expression, and infiltration of inflammatory cells. In conclusion, increased mitochondrial oxygen consumption results in kidney hypoxia and subsequent nephropathy. Importantly, these results demonstrate that kidney tissue hypoxia, per se, without confounding hyperglycemia or oxidative stress, may be sufficient to initiate the development of nephropathy and therefore demonstrate a new interventional target for treating kidney disease.

  • 19.
    Friederich-Persson, Malou
    et al.
    Uppsala University, Sweden.
    Welch, William J.
    Georgetown University, DC 20007 USA.
    Luo, Zaiming
    Georgetown University, DC 20007 USA.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Uppsala University, Sweden.
    Nordquist, Lina
    Uppsala University, Sweden.
    Angiotensin II Reduces Transport-Dependent Oxygen Consumption but Increases Transport-Independent Oxygen Consumption in Immortalized Mouse Proximal Tubular Cells2014In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 812, p. 157-163Article in journal (Refereed)
    Abstract [en]

    Oxidative stress is closely associated with renal dysfunction following diabetes and hypertension. Angiotensin II (Ang II) can activate the NADPH-oxidase, increasing oxidative stress that is thought to blunt proximal tubular electrolyte transport and thereby oxygen consumption (QO(2)). We investigated the effect of Ang II on QO(2) in immortalized mouse proximal tubular cells over-expressing the NADPH oxidase subunit p22(phox); a model of increased oxidative stress. Cultured cells were exposed to either Ang II or H2O2 for 48 h. QO(2) was determined during baseline (113 mmol/l NaCl; transport-dependent QO(2)) and during sodium-free conditions (transport-independent QO(2)). Ang II reduced transport-dependent QO(2) in wild-types, but not in p22(phox) which also displayed increased QO(2) at baseline. Transport-independent QO(2) was increased in p22(phox) and Ang II had no additional effect, whereas it increased QO(2) in wild-type. Addition of H2O2 reduced transport-dependent QO(2) in wild-types, but not in p22(phox). Transport-independent QO(2) was unaffected by H2O2. The similar effects of Ang II and H2O2 to reduce transport-dependent QO(2) suggest a direct regulatory role of oxidative stress. In accordance, the transport-dependent QO(2) was reduced in p22(phox) already during baseline. The effects of Ang II on transport-independent QO(2) was not replicated by H2O2, indicating direct regulation via Ang II-receptors independently of oxidative stress. However, the Ang II effect was absent in p22(phox), suggesting that oxidative stress also modulates normal Ang II signaling. In conclusion, Ang II affects both transport-dependent and transport-independent QO(2) in proximal tubular cells and may be an important pathway modulating renal QO(2).

  • 20.
    Hansell, P.
    et al.
    Uppsala University, Sweden.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Uppsala University, Sweden.
    A role for the extracellular matrix component hyaluronan in kidney dysfunction during ACE-inhibitor fetopathy2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 213, no 4, p. 795-804Article, review/survey (Refereed)
    Abstract [en]

    Despite data showing that inhibitors of the renin-angiotensin system increase the risks of fetal morbidity and dysfunctionality later in life, their use during pregnancy has increased. The fetopathy induced by angiotensin converting enzyme (ACE) inhibitors is characterized by anuria, hypotension and growth restriction, but can also be associated with pulmonary hypoplasia. In the kidney, this fetopathy includes atrophy of the medulla, reduced number of glomeruli, developmental lesions of tubules and vessels, tubulointerstitial inflammation and extracellular matrix accumulation. Although angiotensin II (Ang II) inhibition during nephrogenesis interferes with normal growth and development, this review will focus on effects of the heavily accumulated matrix component hyaluronan (HA). An important mechanism of HA accumulation during nephrogenesis is disruption of its normal reduction as a consequence of lack of Ang II activation of hyaluronidase. Hyaluronan has very large water-attracting properties and is pro-inflammatory when fragmented. The ensuing inflammation and interstitial oedema affect kidney function. Hyaluronan is colocalized with CD44 overexpression and infiltrating immune cells. These properties make HA a plausible contributor to the observed structural and functional kidney defects associated with the fetopathy. Available data support an involvement of HA in kidney dysfunction of the foetus and during adulthood due to the physico-chemical characteristics of HA. No clinical treatment for HA accumulation exists. Treatment with the HA-degrading enzyme hyaluronidase and an HA synthesis inhibitor has been tested successfully in experimental models in the kidney, heart and pancreas. Reduced HA accumulation to reduce interstitial oedema and inflammation may improve organ function, but this concept needs to be tested in a controlled study before causal relationships can be established.

  • 21.
    Hansell, Peter
    et al.
    Uppsala University, Sweden .
    Welch, William J.
    Georgetown University, DC, USA .
    Blantz, Roland C.
    University of California San Diego, CA, USA.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Determinants of kidney oxygen consumption and their relationship to tissue oxygen tension in diabetes and hypertension2013In: Clinical and experimental pharmacology & physiology, ISSN 0305-1870, E-ISSN 1440-1681, Vol. 40, no 2, p. 123-137Article, review/survey (Refereed)
    Abstract [en]

    The high renal oxygen (O2) demand is associated primarily with tubular O2 consumption (Qo2) necessary for solute reabsorption. Increasing O2 delivery relative to demand via increased blood flow results in augmented tubular electrolyte load following elevated glomerular filtration, which, in turn, increases metabolic demand. Consequently, elevated kidney metabolism results in decreased tissue oxygen tension. The metabolic efficiency for solute transport (Qo2/TNa) varies not only between different nephron sites, but also under different conditions of fluid homeostasis and disease. Contributing mechanisms include the presence of different Na+ transporters, different levels of oxidative stress and segmental tubular dysfunction. Sustained hyperglycaemia results in increased kidney Qo2, partly due to mitochondrial dysfunction and reduced electrolyte transport efficiency. This results in intrarenal tissue hypoxia because the increased Qo2 is not matched by a similar increase in O2 delivery. Hypertension leads to renal hypoxia, mediated by increased angiotensin receptor tonus and oxidative stress. Reduced uptake in the proximal tubule increases load to the thick ascending limb. There, the increased load is reabsorbed, but at greater O2 cost. The combination of hypertension, angiotensin II and oxidative stress initiates events leading to renal damage and reduced function. Tissue hypoxia is now recognized as a unifying pathway to chronic kidney disease. We have gained good knowledge about major changes in O2 metabolism occurring in diabetic and hypertensive kidneys. However, further efforts are needed to elucidate how these alterations can be prevented or reversed before translation into clinical practice.

  • 22. Helle, Frank
    et al.
    Hultström, Michael
    Skogstrand, Trude
    Palm, Fredrik
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Iversen, Bjarne
    Angiotensin II-induced contraction is attenuated by nitric oxide in afferent arterioles from the nonclipped kidney in 2K1C2009In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 296, no 1, p. F78-F86Article in journal (Refereed)
    Abstract [en]

    Two-kidney, one-clip (2K1C) is a model of renovascular hypertension where we previously found an exaggerated intracellular calcium (Ca(i)(2+)) response to ANG II in isolated afferent arterioles (AAs) from the clipped kidney (Helle F, Vagnes OB, Iversen BM. Am J Physiol Renal Physiol 291: F140-F147, 2006). To test whether nitric oxide (NO) ameliorates the exaggerated ANG II response in 2K1C, we studied ANG II (10(-7) mol/l)-induced calcium signaling and contractility with or without the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME). In AAs from the nonclipped kidney, l-NAME increased the ANG II-induced Ca(i)(2+) response from 0.28 +/- 0.05 to 0.55 +/- 0.09 (fura 2, 340 nm/380 nm ratio) and increased contraction from 80 +/- 6 to 60 +/- 6% of baseline (P < 0.05). In vessels from sham and clipped kidneys, l-NAME had no effect. In diaminofluorescein-FM diacetate-loaded AAs from the nonclipped kidney, ANG II increased NO-derived fluorescence to 145 +/- 34% of baseline (P < 0.05 vs. sham), but not in vessels from the sham or clipped kidney. Endothelial NOS (eNOS) mRNA and ser-1177 phosphorylation were unchanged in both kidneys from 2K1C, while eNOS protein was reduced in the clipped kidney compared with sham. Cationic amino acid transferase-1 and 2 mRNAs were increased in 2K1C, indicating increased availability of l-arginine for NO synthesis, but counteracted by decreased scavenging of the eNOS inhibitor asymmetric dimethylarginine by dimethylarginine dimethylaminohydrolase 2. In conclusion, the Ca(i)(2+) and contractile responses to ANG II are blunted by NO release in the nonclipped kidney. This may protect the nonclipped kidney from the hypertension and elevated ANG II levels in 2K1C.

  • 23.
    Helle, Frank
    et al.
    University of Bergen, Norway .
    Skogstrand, Trude
    University of Bergen, Norway .
    Schwartz, Idit F.
    Tel Aviv University, Israel .
    Schwartz, Doron
    Tel Aviv University, Israel .
    Iversen, Bjarne M.
    University of Bergen, Norway .
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Hultstrom, Michael
    University of Bergen, Norway .
    Nitric oxide in afferent arterioles after uninephrectomy depends on extracellular L-arginine2013In: AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, ISSN 1931-857X, Vol. 304, no 8, p. F1088-F1098Article in journal (Refereed)
    Abstract [en]

    Helle F, Skogstrand T, Schwartz IF, Schwartz D, Iversen BM, Palm F, Hultstrom M. Nitric oxide in afferent arterioles after uninephrectomy depends on extracellular L-arginine. Am J Physiol Renal Physiol 304: F1088-F1098, 2013. First published February 13, 2013; doi: 10.1152/ajprenal.00665.2011.-Uninephrectomy (UNX) causes hyperperfusion of the contralateral remaining kidney via increased nitric oxide (NO) synthesis. Although the exact mechanism remains largely unknown, we hypothesize that this would be localized to the afferent arteriole and that it depends on cellular uptake of L-arginine. The experiments were performed in rats 2 days (early) or 6 wk (late) after UNX and compared with controls (Sham) to study acute and chronic effects on NO metabolism. Renal blood flow was increased after UNX (21 +/- 2 ml.min(-1).kg(-1) in sham, 30 +/- 3 in early, and 26 +/- 1 in late, P andlt; 0.05). NO inhibition with N-omega-nitro-L-arginine methyl ester hydrochloride (L-NAME) caused a greater increase in renal vascular resistance in early UNX compared with Sham and late UNX (138 +/- 24 vs. 88 +/- 10, and 84 +/- 7%, P andlt; 0.01). The lower limit of autoregulation was increased both in early and late UNX compared with Sham (P andlt; 0.05). L-NAME did not affect the ANG II-induced contraction of isolated afferent arterioles (AA) from Sham. AA from early UNX displayed a more pronounced contraction in response to L-NAME (-57 +/- 7 vs. -16 +/- 7%, P andlt; 0.05) and in the absence of L-arginine (-41 +/- 4%, P andlt; 0.05) compared with both late UNX and Sham. mRNA expression of endothelial NO synthase was reduced, whereas protein expression was unchanged. Cationic amino acid transporter-1 and -2 mRNA was increased, while protein was unaffected in isolated preglomerular resistance vessels. In conclusion, NO-dependent hyperperfusion of the remaining kidney in early UNX is associated with increased NO release from the afferent arteriole, which is highly dependent on extracellular L-arginine availability.

  • 24.
    Lai, En Yin
    et al.
    Georgetown University, USA.
    Luo, Zaiming
    Georgetown University, USA.
    Onozato, Maristela L
    Georgetown University, USA.
    Rudolph, Earl H
    Georgetown University, USA.
    Solis, Glenn
    Georgetown University, USA.
    Jose, Pedro A
    George Washington University, USA.
    Wellstein, Anton
    Georgetown University, USA.
    Aslam, Shakil
    Georgetown University, USA.
    Quinn, Mark T
    Montana State University, USA.
    Griendling, Kathy
    Emory University, Atlanta, Georgia, USA.
    Le, Thu
    University of Virginia, Charlottesville, USA.
    Li, Ping
    Georgetown University, USA.
    Palm, Fredrik
    Division of Nephrology and Hypertension, Center for Hypertension, Kidney and Vascular Research, Georgetown University, USA.
    Welch, William J
    Georgetown University, USA.
    Wilcox, Christopher S
    Georgetown University, USA.
    Effects of the antioxidant drug tempol on renal oxygenation in mice with reduced renal mass2012In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 303, no 1, p. F64-74Article in journal (Refereed)
    Abstract [en]

    We tested the hypothesis that reactive oxygen species (ROS) contributed to renal hypoxia in C57BL/6 mice with &frac56; surgical reduction of renal mass (RRM). ROS can activate the mitochondrial uncoupling protein 2 (UCP-2) and increase O(2) usage. However, UCP-2 can be inactivated by glutathionylation. Mice were fed normal (NS)- or high-salt (HS) diets, and HS mice received the antioxidant drug tempol or vehicle for 3 mo. Since salt intake did not affect the tubular Na(+) transport per O(2) consumed (T(Na/)Q(O2)), further studies were confined to HS mice. RRM mice had increased excretion of 8-isoprostane F(2α) and H(2)O(2), renal expression of UCP-2 and renal O(2) extraction, and reduced T(Na/)Q(O2) (sham: 20 ± 2 vs. RRM: 10 ± 1 μmol/μmol; P < 0.05) and cortical Po(2) (sham: 43 ± 2, RRM: 29 ± 2 mmHg; P < 0.02). Tempol normalized all these parameters while further increasing compensatory renal growth and glomerular volume. RRM mice had preserved blood pressure, glomeruli, and patchy tubulointerstitial fibrosis. The patterns of protein expression in the renal cortex suggested that RRM kidneys had increased ROS from upregulated p22(phox), NOX-2, and -4 and that ROS-dependent increases in UCP-2 led to hypoxia that activated transforming growth factor-β whereas erythroid-related factor 2 (Nrf-2), glutathione peroxidase-1, and glutathione-S-transferase mu-1 were upregulated independently of ROS. We conclude that RRM activated distinct processes: a ROS-dependent activation of UCP-2 leading to inefficient renal O(2) usage and cortical hypoxia that was offset by Nrf-2-dependent glutathionylation. Thus hypoxia in RRM may be the outcome of NADPH oxidase-initiated ROS generation, leading to mitochondrial uncoupling counteracted by defense pathways coordinated by Nrf-2.

  • 25.
    Laustsen, Christoffer
    et al.
    Department of Clinical Medicine, MR Research Centre, Aarhus University, Aarhus, Denmark.
    Lipsø, Kasper
    Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark Department of Electrical Engineering, Technical University of Denmark, Kgs. Lyngby, Denmark.
    Ostergaard, Jakob Appel
    Department of Endocrinology and Internal Medicine and Danish Diabetes Academy, Aarhus University Hospital, Aarhus, Denmark Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark.
    Nørregaard, Rikke
    Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark.
    Flyvbjerg, Allan
    Department of Endocrinology and Internal Medicine and Danish Diabetes Academy, Aarhus University Hospital, Aarhus, Denmark Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark.
    Pedersen, Michael
    Department of Clinical Medicine, MR Research Centre, Aarhus University, Aarhus, Denmark Comparative Medicine Lab, Aarhus University, Aarhus, Denmark.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
    Ardenkjær-Larsen, Jan Henrik
    Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark Department of Electrical Engineering, Technical University of Denmark, Kgs. Lyngby, Denmark GE Healthcare, Broendby, Denmark.
    Insufficient insulin administration to diabetic rats increases substrate utilization and maintains lactate production in the kidney.2014In: Physiological Reports, E-ISSN 2051-817X, ISSN 2051-817X, Vol. 2, no 12Article in journal (Refereed)
    Abstract [en]

    Good glycemic control is crucial to prevent the onset and progression of late diabetic complications, but insulin treatment often fails to achieve normalization of glycemic control to the level seen in healthy controls. In fact, recent experimental studies indicate that insufficient treatment with insulin, resulting in poor glycemic control, has an additional effect on progression of late diabetic complications, than poor glycemic control on its own. We therefore compared renal metabolic alterations during conditions of poor glycemic control with and without suboptimal insulin administration, which did not restore glycemic control, to streptozotocin (STZ)-diabetic rats using noninvasive hyperpolarized (13)C-pyruvate magnetic resonance imaging (MRI) and blood oxygenation level-dependent (BOLD) (1)H-MRI to determine renal metabolic flux and oxygen availability, respectively. Suboptimal insulin administration increased pyruvate utilization and metabolic flux via both anaerobic and aerobic pathways in diabetic rats even though insulin did not affect kidney oxygen availability, HbA1c, or oxidative stress. These results imply direct effects of insulin in the regulation of cellular substrate utilization and metabolic fluxes during conditions of poor glycemic control. The study demonstrates that poor glycemic control in combination with suboptimal insulin administration accelerates metabolic alterations by increasing both anaerobic and aerobic metabolism resulting in increased utilization of energy substrates. The results demonstrate the importance of tight glycemic control in insulinopenic diabetes, and that insulin, when administered insufficiently, adds an additional burden on top of poor glycemic control.

  • 26.
    Laustsen, Christoffer
    et al.
    Aarhus University, Denmark; Copenhagen University Hospital Hvidovre, Denmark .
    Lycke, Sara
    Uppsala University, Sweden .
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Uppsala University, Sweden .
    Østergaard, Jakob A.
    Aarhus University Hospital, Denmark; Aarhus University, Denmark.
    Bibby, Bo M.
    Aarhus University, Denmark .
    Nørrregaard, Rikke
    Aarhus University, Denmark .
    Flyvbjerg, Allan
    Aarhus University Hospital, Denmark; Aarhus University, Denmark .
    Pedersen, Michael
    Aarhus University, Denmark; Aarhus University, Denmark .
    Ardenkjaer-Larsen, Jan H.
    Copenhagen University Hospital Hvidovre, Denmark; GE Healthcare, Copenhagen, Denmark;Technical University of Denmark, Kgs Lyngby.
    High altitude may alter oxygen availability and renal metabolism in diabetics as measured by hyperpolarized [1-C-13]pyruvate magnetic resonance imaging2014In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 86, no 1, p. 67-74Article in journal (Refereed)
    Abstract [en]

    The kidneys account for about 10% of the whole body oxygen consumption, whereas only 0.5% of the total body mass. It is known that intrarenal hypoxia is present in several diseases associated with development of kidney disease, including diabetes, and when renal blood flow is unaffected. The importance of deranged oxygen metabolism is further supported by deterioration of kidney function in patients with diabetes living at high altitude. Thus, we argue that reduced oxygen availability alters renal energy metabolism. Here, we introduce a novel magnetic resonance imaging (MRI) approach to monitor metabolic changes associated with diabetes and oxygen availability. Streptozotocin diabetic and control rats were given reduced, normal, or increased inspired oxygen in order to alter tissue oxygenation. The effects on kidney oxygen metabolism were studied using hyperpolarized [1-C-13]pyruvate MRI. Reduced inspired oxygen did not alter renal metabolism in the control group. Reduced oxygen availability in the diabetic kidney altered energy metabolism by increasing lactate and alanine formation by 23% and 34%, respectively, whereas the bicarbonate flux was unchanged. Thus, the increased prevalence and severity of nephropathy in patients with diabetes at high altitudes may originate from the increased sensitivity toward inspired oxygen. This increased lactate production shifts the metabolic routs toward hypoxic pathways.

  • 27. Lindahl, Emma
    et al.
    Nordquist, Lina
    Uppsala universitet, Integrativ Fysiologi.
    Müller, Patrick
    El Agha, Eli
    Friederich, Malou
    Uppsala universitet, Integrativ Fysiologi.
    Dahlman-Wright, Karin
    Palm, Fredrik
    Uppsala universitet, Integrativ Fysiologi.
    Jörnvall, Hans
    Early transcriptional regulation by C-peptide in freshly isolated rat proximal tubular cells2011In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 27, no 7, p. 697-704Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Clinical studies have shown that proinsulin C-peptide exerts renoprotective effects in type 1 diabetes, although the underlying mechanisms are poorly understood. As C-peptide has been shown to induce several intracellular events and to localize to nuclei, we aimed to determine whether gene transcription is affected in proximal tubular kidney cells, and if so, whether genes with altered transcription include those related to protective mechanisms. METHODS: The effect of C-peptide incubation (2h) on gene expression was investigated in freshly isolated proximal tubular cells from streptozotocin-diabetic Sprague-Dawley rats using global gene expression profiling and RT-qPCR. Protein expression was assayed using western blotting. Different bioinformatic strategies were employed. RESULTS: Gene transcription profiling demonstrated differential transcription of 492 genes (p<0.01) after 2h of C-peptide exposure, with the majority of these genes repressed (83%). RT-qPCR validation supported a trend of several GPCR's being activated, and certain transcription factors to be repressed. Also, C-peptide repressed the transcription of genes associated with pathways of circulatory and inflammatory diseases. CONCLUSIONS: This study shows that C-peptide exerts early effects on gene transcription in proximal tubular cells. The findings also bring further knowledge to the renoprotective mechanisms of C-peptide in type I diabetes, and supports a transcriptional activity for C-peptide. It is suggested that C-peptide may play a regulatory role in the gene expression of proximal tubular cells.

  • 28.
    Liss, Per
    et al.
    Uppsala universitet, Institutionen för onkologi, radiologi och klinisk immunologi.
    Aukland, Knut
    Carlsson, Per-Ola
    Institutionen för medicinsk cellbiologi.
    Palm, Fredrik
    Institutionen för medicinsk cellbiologi.
    Hansell, Peter
    Institutionen för medicinsk cellbiologi.
    Influence of iothalamate on renal medullary perfusion and oxygenation in the rat.2005In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 46, no 8, p. 823-9Article in journal (Other academic)
  • 29.
    Liss, Per
    et al.
    Uppsala universitet, Enheten för radiologi.
    Hansell, Peter
    Uppsala universitet, Integrativ Fysiologi.
    Carlsson, Per-Ola
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Fasching, Angelica
    Uppsala universitet, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Integrativ Fysiologi.
    Iodinated contrast media decrease renomedullary blood flow. A possible cause of contrast media-induced nephropathy2009In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 645, p. 213-218Article in journal (Refereed)
    Abstract [en]

    The renal medulla has been implicated as a key target for contrast media-induced nephropathy (CIN). Although the effects of contrast media (CM) on whole kidney blood flow are well characterized, the effect of CM on renal medullary blood flow has been controversial. It has been reported that an extremely high dose of a high osmolar CM (iothalamate; 2900 mg I/kg bw) injected rapidly increased the renal outer medullary blood flow (OMBF). However, more clinical relevant doses consistently result in a sustained decrease in medullary blood flow. Furthermore, simultaneous measurements using both laser-Doppler flowmetry and hydrogen washout yield similar results of a decrease in OMBF after CM administration. CM induced a transient 28% decrease in the laser-Doppler signal from the outer medulla, while the hydrogen washout rate in the same region was reduced by approximately 50%. Furthermore, CM administration consistently results in decreased medullary oxygen tension (PO2). The renal medulla works already during normal physiological conditions at the verge of hypoxia, and the majority of the studies published so far are in agreement with the hypothesis that CIN may have its origin in a further reduction in blood flow and/or oxygen availability of this region of the kidney.

  • 30.
    Liss, Per
    et al.
    University of Uppsala Hospital, Sweden.
    Hansell, Peter
    Uppsala University, Sweden.
    Fasching, Angelica
    Uppsala University, Sweden.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Uppsala University, Sweden.
    Iodinated contrast media inhibit oxygen consumption in freshly isolated proximal tubular cells from elderly humans and diabetic rats: Influence of nitric oxide2016In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 121, no 1, p. 12-16Article in journal (Refereed)
    Abstract [en]

    Objectives Mechanisms underlying contrast medium (CM)-induced nephropathy remain elusive, but recent attention has been directed to oxygen availability. The purpose of this study was to evaluate the effect of the low-osmolar CM iopromide and the iso-osmolar CM iodixanol on oxygen consumption (QO(2)) in freshly isolated proximal tubular cells (PTC) from kidneys ablated from elderly humans undergoing nephrectomy for renal carcinomas and from normoglycemic or streptozotocin-diabetic rats. Materials PTC were isolated from human kidneys, or kidneys of normoglycemic or streptozotocin-diabetic rats. QO(2) was measured with Clark-type microelectrodes in a gas-tight chamber with and without each CM (10 mg I/mL medium). L-NAME was used to inhibit nitric oxide (NO) production caused by nitric oxide synthase. Results Both CM reduced QO(2) in human PTC (about -35%) which was prevented by L-NAME. PTC from normoglycemic rats were unaffected by iopromide, whereas iodixanol decreased QO(2) (-34%). Both CM decreased QO(2) in PTC from diabetic rats (-38% and -36%, respectively). L-NAME only prevented the effect of iopromide in the diabetic rat PTC. Conclusions These observations demonstrate that CM can induce NO release from isolated PTC in vitro, which affects QO(2). Our results suggest that the induction of NO release and subsequent effect on the cellular oxygen metabolism are dependent on several factors, including CM type and pre-existing risk factors for the development of CM-induced nephropathy.

  • 31. Marteyn, Benoit
    et al.
    West, Nicholas P.
    Browning, Douglas F.
    Cole, Jeffery A.
    Shaw, Jonathan G.
    Palm, Fredrik
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Mounier, Joelle
    Prevost, Marie-Christine
    Sansonetti, Philippe
    Tang, Christoph M.
    Modulation of Shigella virulence in response to available oxygen in vivo2010In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 465, no 7296, p. 355-358Article in journal (Refereed)
    Abstract [en]

    Bacteria coordinate expression of virulence determinants in response to localized microenvironments in their hosts. Here we show that Shigella flexneri, which causes dysentery, encounters varying oxygen concentrations in the gastrointestinal tract, which govern activity of its type three secretion system (T3SS). The T3SS is essential for cell invasion and virulence(1). In anaerobic environments (for example, the gastrointestinal tract lumen), Shigella is primed for invasion and expresses extended T3SS needles while reducing Ipa (invasion plasmid antigen) effector secretion. This is mediated by FNR (fumarate and nitrate reduction), a regulator of anaerobic metabolism that represses transcription of spa32 and spa33, virulence genes that regulate secretion through the T3SS. We demonstrate there is a zone of relative oxygenation adjacent to the gastrointestinal tract mucosa, caused by diffusion from the capillary network at the tips of villi. This would reverse the anaerobic block of Ipa secretion, allowing T3SS activation at its precise site of action, enhancing invasion and virulence.

  • 32. Melican, K
    et al.
    Boekel, J
    Månsson, LE
    Sandoval, RM
    Tanner, GA
    Källskog, Örjan
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Palm, Fredrik
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Molitoris, Bruce
    Richter-Dahlfors, Agneta
    Bacterial infection-mediated mucosal signalling induces local renal ischaemia as a defence against sepsis2008In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 10, no 10, p. 1987-1998Article in journal (Refereed)
    Abstract [en]

    Ascending urinary tract infections can cause extensive damage to kidney structure and function. We have used a number of advanced techniques including multiphoton microscopy to investigate the crucial early phases of uropathogenic Escherichia coli induced pyelonephritis within a living animal. Our results reveal a previously undescribed innate vascular response to mucosal infection, allowing isolation and eradication of the pathogen. The extremely rapid host response to mucosal infection was highlighted by the triggering of a cascade of events within 3-4 h. Epithelial signalling produced an increase in cellular O-2 consumption and affected microvascular flow by clotting, causing localized ischaemia. Subsequent ischaemic damage affected pathophysiology with actin re-arrangement and epithelial sloughing leading to paracellular bacterial movement. A denuded tubular basement membrane is shown to hinder immediate dissemination of bacteria, giving the host time to isolate the infection by clotting. Suppression of clotting by heparin treatment caused fatal urosepsis. Clinically these findings may be relevant in antibiotics delivery in pyelonephritis patients and to the use of anticoagulants in sepsis.

  • 33.
    Melville, J. M.
    et al.
    Uppsala University, Sweden.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Uppsala University, Sweden.
    Hultstrom, M.
    Uppsala University, Sweden.
    Editorial Material: Renal oxygenation during haemorrhage is not aggravated by angiotensin II AT1-receptor blockade in ACTA PHYSIOLOGICA, vol 216, issue 2, pp 153-1552016In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 216, no 2, p. 153-155Article in journal (Other academic)
    Abstract [en]

    n/a

  • 34.
    Nordquist, Lina
    et al.
    Uppsala universitet, Integrativ Fysiologi.
    Brown, Russell
    Uppsala universitet, Integrativ Fysiologi.
    Fasching, Angelica
    Uppsala universitet, Integrativ Fysiologi.
    Sjöquist, Mats
    Uppsala universitet, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Integrativ Fysiologi.
    Proinsulin C-peptide reduces diabetes-induced glomerular hyperfiltration via efferent arteriole dilation and inhibition of tubular sodium reabsorption2009In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 297, no 5, p. F1265-F1272Article in journal (Refereed)
    Abstract [en]

    C-peptide reduces diabetes-induced glomerular hyperfiltration in diabetic patients and experimental animal models. However, the mechanisms mediating the beneficial effect of C-peptide remain unclear. We investigated whether altered renal afferent-efferent arteriole tonus or alterations in tubular Na+ transport (T(Na)) in response to C-peptide administration mediate the reduction of diabetes-induced glomerular hyperfiltration. Glomerular filtration rate, filtration fraction, total and cortical renal blood flow, total kidney O2 consumption (QO2), T(Na), fractional Na+ and Li+ excretions, and tubular free-flow and stop-flow pressures were measured in anesthetized adult male normoglycemic and streptozotocin-diabetic Sprague-Dawley rats. The specific effect of C-peptide on transport-dependent QO2 was investigated in vitro in freshly isolated proximal tubular cells. C-peptide reduced glomerular filtration rate (-24%), stop-flow pressure (-8%), and filtration fraction (-17%) exclusively in diabetic rats without altering renal blood flow. Diabetic rats had higher baseline T(Na) (+40%), which was reduced by C-peptide. Similarly, C-peptide increased fractional Na+ (+80%) and Li+ (+47%) excretions only in the diabetic rats. None of these parameters was affected by vehicle treatments in either group. Baseline QO2 was 37% higher in proximal tubular cells from diabetic rats than controls and was normalized by C-peptide. C-peptide had no effect on ouabain-pretreated diabetic cells from diabetic rats. C-peptide reduced diabetes-induced hyperfiltration via a net dilation of the efferent arteriole and inhibition of tubular Na+ reabsorption, both potent regulators of the glomerular net filtration pressure. These findings provide new mechanistic insight into the beneficial effects of C-peptide on diabetic kidney function.

  • 35.
    Nordquist, Lina
    et al.
    Uppsala University, Sweden.
    Friederich-Persson, Malou
    Uppsala University, Sweden.
    Fasching, Angelica
    Uppsala University, Sweden.
    Liss, Per
    Uppsala University, Sweden.
    Shoji, Kumi
    University of Tokyo, Japan.
    Nangaku, Masaomi
    University of Tokyo, Japan.
    Hansell, Peter
    Uppsala University, Sweden.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Uppsala University, Sweden.
    Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy2015In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 26, no 2, p. 328-338Article in journal (Refereed)
    Abstract [en]

    Hyperglycemia results in increased oxygen consumption and decreased oxygen tension in the kidney. We tested the hypothesis that activation of hypoxia-inducible factors (HIFs) protects against diabetes-induced alterations in oxygen metabolism and kidney function. Experimental groups consisted of control and streptozotocin-induced diabetic rats treated with or without chronic cobalt chloride to activate HIFs. We elucidated the involvement of oxidative stress by studying the effects of acute administration of the superoxide dismutase mimetic tempol. Compared with controls, diabetic rats displayed tissue hypoxia throughout the kidney, glonnerular hyperfiltration, increased oxygen consumption, increased total mitochondrial leak respiration, and decreased tubular sodium transport efficiency. Diabetic kidneys showed proteinuria and tubulointerstitial damage. Cobalt chloride activated HIFs, prevented the diabetes-induced alterations in oxygen metabolism, mitochondrial leak respiration, and kidney function, and reduced proteinuria and tubulointerstitial damage. The beneficial effects of tempol were less pronounced after activation of HIFs, indicating improved oxidative stress status. In conclusion, activation of HIFs prevents diabetes-induced alteration in kidney oxygen metabolism by normalizing glomerular filtration, which reduces tubular electrolyte load, preventing mitochondrial leak respiration and improving tubular transport efficiency. These improvements could be related to reduced oxidative stress and account for the reduced proteinuria and tubulointerstitial damage. Thus, pharnnacologic activation of the HIF system may prevent development of diabetic nephropathy.

  • 36.
    Nordquist, Lina
    et al.
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Kallas, Åsa
    Stridh, Sara
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Palm, Fredrik
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Wahren, John
    Renoprotective Effects of C-Peptide on Type 1 Diabetes2011In: Diabetes and C-peptide: Scientific and Clinical Aspects / [ed] Sima Anders A.F., New York, NY: Humana Press/Springer Science , 2011, 1, p. 67-78Chapter in book (Refereed)
  • 37.
    Nordquist, Lina
    et al.
    Division of Integrative Physiology, Departments of Medical Cell Biology, Uppsala University.
    Liss, Per
    Radiology, Oncology and Radiation Science, Uppsala University.
    Fasching, Angelica
    Division of Integrative Physiology, Departments of Medical Cell Biology, Uppsala University.
    Hansell, Peter
    Division of Integrative Physiology, Departments of Medical Cell Biology, Uppsala University.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Division of Integrative Physiology, Departments of Medical Cell Biology, Uppsala University, Biomedical Center.
    Hypoxia in the diabetic kidney is independent of advanced glycation end-products.2013In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 765, p. 185-193Article in journal (Refereed)
    Abstract [en]

    Sustained hyperglycemia is closely associated with increased risk to develop nephropathy. We have previously reported alterations in the intrarenal oxygen metabolism already after the early onset of diabetes. Furthermore, formation of advanced glycation end-products (AGE) is postulated as a major contributor to diabetic nephropathy. We therefore investigated the possible relationship between altered oxygen metabolism and AGE in diabetic kidneys.Normoglycemic and streptozotocin-diabetic rats with and without chronic treatment with aminoguanidine (AGE inhibitor; 600 mg/kg bw/24 h in drinking water) or L-N(6)-(1-Iminoethyl)lysine (L-NIL, iNOS inhibitor, 1 mg/kg bw/24 h in drinking water) were studied 2 weeks after induction of diabetes. Glomerular filtration rate (GFR) was estimated by inulin clearance, oxygen tension (pO(2)) and interstitial pH by microelectrodes and regional renal blood flow (RBF) by laser-Doppler. Histological changes were evaluated on fixed tissue.Glomerular hyperfiltration was unaffected by aminoguanidine, whereas L-NIL normalized GFR in diabetic rats. pO(2) and interstitial pH, but not RBF, were lower in both kidney cortex and medulla compared to control rats, but was unaffected by both chronic treatments. Urinary protein excretion was higher in diabetic rats and unaffected by L-NIL, whereas aminoguanidine paradoxically increased this parameter. Damage scores were similar in all groups.In conclusion, diabetes-induced alterations in intrarenal oxygen metabolism are independent of the AGE pathway, and precede any morphological changes. These findings highlight the early stage of diabetes as being a metabolic disorder also in the kidney.

  • 38.
    Nordquist, Lina
    et al.
    Uppsala universitet, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Integrativ Fysiologi.
    Diabetes-induced alterations in renal medullary microcirculation and metabolism2007In: Current diabetes reviews, ISSN 1573-3998, Vol. 3, no 1, p. 53-65Article, review/survey (Refereed)
    Abstract [en]

    Diabetes-induced renal complications, i.e. diabetes nephropathy, are a major cause of morbidity and mortality. The exact mechanisms mediating the negative influence of hyperglycemia on renal function are unclear, although several hypotheses have been postulated. Cellular mechanisms include glucose-induced excessive formation of reactive oxygen species, increased glucose flux through polyol pathway and pentose phosphate shunt, formation of advanced glycation end-products and activation of protein kinase C and NADPH oxidase. However, the renal effects in vivo of each and every one of these mechanisms are less clear, although recent studies have shown several major alterations predominantly in the renal medulla as a result of sustained hyperglycemia. Already during normal conditions, the renal medulla has a remarkably low oxygen tension (PO2) and a high degree of non-oxygen dependent energy metabolism. Alterations in either blood perfusion or oxygen delivery to the medullary region will have significant effects on both regional metabolism and total kidney function. Recently, sustained hyperglycemia has been shown to induce a pronounced reduction in preferentially renal medullary PO2. This review will present the current knowledge of diabetes-induced alterations in renal medullary metabolism and function, but also discuss future targets for prevention of diabetic nephropathy.

  • 39.
    Nordquist, Lina
    et al.
    Uppsala universitet, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Integrativ Fysiologi.
    Andresen, Bradley T
    Renal and vascular benefits of C-peptide: Molecular mechanisms of C-peptide action2008In: Biologics: Targets & Therapy, ISSN 1177-5475, E-ISSN 1177-5491, Vol. 2, no 3, p. 441-452Article in journal (Refereed)
    Abstract [en]

    C-peptide has long been thought to be an inert byproduct of insulin production, but it has become apparent, and accepted, that C-peptide has important biological properties. C-peptide displays beneficial effects in many tissues affected by diabetic complications, such as increased peripheral blood flow and protection from renal damage. However, the mechanisms mediating these effects remain unclear. C-peptide interacts with cellular membranes at unidentified sites distinctive of the insulin family of receptors, and signals to multiple targets known to play a role in diabetes and diabetic complications, such as Na(+)/K(+)-ATPase and NOS. In general, the physiological and molecular effects of C-peptide resemble insulin, but C-peptide also possesses traits separate from those of insulin. These basic studies have been confirmed in human studies, suggesting that C-peptide may lend itself to clinical applications. However, the molecular and physiological properties of C-peptide are not completely elucidated, and large clinical studies have not begun. In order to further these goals, we critically summarize the current state of knowledge regarding C-peptide's renal and vascular effects and the molecular signaling of C-peptide.

  • 40.
    ONeill, Julie
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Fasching, Angelica
    Uppsala University, Sweden.
    Pihl, Liselotte
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Patinha, Daniela
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Franzén, Stephanie
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Uppsala University, Sweden.
    Acute SGLT inhibition normalizes O-2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats2015In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 309, no 3, p. F227-F234Article in journal (Refereed)
    Abstract [en]

    Early stage diabetic nephropathy is characterized by glomerular hyperfiltration and reduced renal tissue PO2. Recent observations have indicated that increased tubular Na+-glucose linked transport (SGLT) plays a role in the development of diabetes-induced hyperfiltration. The aim of the present study was to determine how inhibition of SLGT impacts upon PO2 in the diabetic rat kidney. Diabetes was induced by streptozotocin in Sprague-Dawley rats 2 wk before experimentation. Renal hemodynamics, excretory function, and renal O-2 homeostasis were measured in anesthetized control and diabetic rats during baseline and after acute SGLT inhibition using phlorizin (200 mg/kg ip). Baseline arterial pressure was similar in both groups and unaffected by SGLT inhibition. Diabetic animals displayed reduced baseline PO2 in both the cortex and medulla. SGLT inhibition improved cortical PO2 in the diabetic kidney, whereas it reduced medullary PO2 in both groups. SGLT inhibition reduced Na+ transport efficiency [tubular Na+ transport (TNa)/renal O-2 consumption (QO(2))] in the control kidney, whereas the already reduced TNa/QO(2) in the diabetic kidney was unaffected by SGLT inhibition. In conclusion, these data demonstrate that when SGLT is inhibited, renal cortex PO2 in the diabetic rat kidney is normalized, which implies that increased proximal tubule transport contributes to the development of hypoxia in the diabetic kidney. The reduction in medullary PO2 in both control and diabetic kidneys during the inhibition of proximal Na+ reabsorption suggests the redistribution of active Na+ transport to less efficient nephron segments, such as the medullary thick ascending limb, which results in medullary hypoxia.

  • 41.
    Onozato, Maristela L
    et al.
    University of Tokyo, Japan and Georgetown University, USA .
    Tojo, Akihiro
    University of Tokyo, Japan.
    Leiper, James
    University College London, UK.
    Fujita, Toshiro
    University of Tokyo, Japan.
    Palm, Fredrik
    Division of Nephrology and Hypertension, Cardiovascular Kidney Hypertension Institutet, Georgetown University, USA.
    Wilcox, Christopher S
    Georgetown University, USA.
    Expression of NG,NG-dimethylarginine dimethylaminohydrolase and protein arginine N-methyltransferase isoforms in diabetic rat kidney: effects of angiotensin II receptor blockers2008In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 57, no 1, p. 172-180Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) is generated by protein arginine N-methyltransferase (PRMT)-1 and is metabolized by N(G),N(G)-dimethylarginine dimethylaminohydrolase (DDAH). We tested the hypothesis that increased serum ADMA (S(ADMA)) in the streptozotocin (STZ)-induced diabetic rat model of diabetes is mediated by an angiotensin receptor blocker-sensitive change in DDAH or PRMT expression.

    RESEARCH DESIGN AND METHODS: Data were compared from four groups of rats: sham-injected controls, untreated STZ-induced diabetic rats at 4 weeks, STZ-induced diabetic rats administered the angiotensin II (Ang II) receptor blocker telmisartan for 2 weeks, and control rats administered telmisartan for 2 weeks.

    RESULTS: Immunostaining and Western blotting of microdissected nephron segments localized DDAH I in the proximal tubules and DDAH II in the glomeruli, afferent arterioles, macula densa, and distal nephron. Renal Ang II and S(ADMA) increased with diabetes but were normalized by 2 weeks of telmisartan. DDAH I expression was decreased in diabetic kidneys, while DDAH II expression was increased. These changes were reversed by telmisartan, which also reduced expression of PRMT-1 and -5. Telmisartan increased expressions of DDAH I but decreased DDAH II in Ang II-stimulated kidney slices ex vivo.

    CONCLUSIONS: Renal Ang II and S(ADMA) are increased in insulinopenic diabetes. They are normalized by an Ang II receptor blocker, which increases the renal expression of DDAH I, decreases PRMT-1, and increases renal NO metabolites.

  • 42.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Uppsala University, Sweden.
    Editorial Material: ET-1 increases reactive oxygen species in hypoxic glomeruli during high salt intake in ACTA PHYSIOLOGICA, vol 213, issue 3, pp 559-5602015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 213, no 3, p. 559-560Article in journal (Other academic)
    Abstract [en]

    n/a

  • 43.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Editorial Material: The dark side of angiotensin II: direct dynamic regulation of the glomerular filtration barrier permeability to macromolecules2012In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 303, no 6, p. F789-F789Article in journal (Other academic)
    Abstract [en]

    n/a

  • 44.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Frontiers in Research Reviews: Kidney Oxygenation in Health and Disease Introduction2013In: Clinical and experimental pharmacology & physiology, ISSN 0305-1870, E-ISSN 1440-1681, Vol. 40, no 2, p. 104-105Article, review/survey (Refereed)
  • 45.
    Palm, Fredrik
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Intrarenal oxygen in diabetes and a possible link to diabetic nephropathy.2006In: Clinical and experimental pharmacology & physiology, ISSN 0305-1870, E-ISSN 1440-1681, Vol. 33, no 10, p. 997-1001Article in journal (Refereed)
  • 46.
    Palm, Fredrik
    et al.
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Bergqvist, David
    Institutionen för kirurgiska vetenskaper.
    Carlsson, Per-Ola
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Hellberg, Olof
    Institutionen för medicinska vetenskaper.
    Nyman, Rickard
    Institutionen för onkologi, radiologi och klinisk immunologi.
    Hansell, Peter
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Liss, Per
    Institutionen för onkologi, radiologi och klinisk immunologi.
    The effects of carbon dioxide versus ioxaglate in the rat kidney.2005In: Journal of Vascular and Interventional Radiology, ISSN 1051-0443, E-ISSN 1535-7732, Vol. 16, no 2 Pt 1, p. 269-74Article in journal (Refereed)
  • 47.
    Palm, Fredrik
    et al.
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Buerk, Donald G.
    Carlsson, Per-Ola
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Hansell, Peter
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Liss, Per
    Uppsala universitet, Institutionen för onkologi, radiologi och klinisk immunologi.
    Reduced nitric oxide concentration in the renal cortex of streptozotocin-induced diabetic rats: effects on renal oxygenation and microcirculation2005In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 54, no 11, p. 3282-7Article in journal (Refereed)
    Abstract [en]

    Nitric oxide (NO) regulates vascular tone and mitochondrial respiration. We investigated the hypothesis that there is reduced NO concentration in the renal cortex of diabetic rats that mediates reduced renal cortical blood perfusion and oxygen tension (P O2). Streptozotocin-induced diabetic and control rats were injected with l-arginine followed by Nomega-nitro-L-arginine-metyl-ester (L-NAME). NO and P O2 were measured using microsensors, and local blood flow was recorded by laser-Doppler flowmetry. Plasma arginine and asymmetric dimethylarginine (ADMA) were analyzed by high-performance liquid chromatography. L-Arginine increased cortical NO concentrations more in diabetic animals, whereas changes in blood flow were similar. Cortical P O2 was unaffected by L-arginine in both groups. L-NAME decreased NO in control animals by 87 +/- 15 nmol/l compared with 45 +/- 7 nmol/l in diabetic animals. L-NAME decreased blood perfusion more in diabetic animals, but it only affected P O2 in control animals. Plasma arginine was significantly lower in diabetic animals (79.7 +/- 6.7 vs. 127.9 +/- 3.9 mmol/l), whereas ADMA was unchanged. A larger increase in renal cortical NO concentration after l-arginine injection, a smaller decrease in NO after L-NAME, and reduced plasma arginine suggest substrate limitation for NO formation in the renal cortex of diabetic animals. This demonstrates a new mechanism for diabetes-induced alteration in renal oxygen metabolism and local blood flow regulation.

  • 48.
    Palm, Fredrik
    et al.
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Carlsson, Per-Ola
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Thick ascending tubular cells in the loop of Henle: regulation of electrolyte homeostasis.2005In: International Journal of Biochemistry and Cell Biology, ISSN 1357-2725, E-ISSN 1878-5875, Vol. 37, no 8, p. 1554-9Article in journal (Refereed)
  • 49.
    Palm, Fredrik
    et al.
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Carlsson, Per-Ola
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Fasching, Angelica
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Hansell, Peter
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Liss, Per
    Uppsala universitet, Enheten för radiologi.
    Diabetes-induced decrease in renal oxygen tension: effects of an altered metabolism2006In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 578, p. 161-166Article in journal (Refereed)
    Abstract [en]

    During conditions with experimental diabetes mellitus, it is evident that several alterations in renal oxygen metabolism occur, including increased mitochondrial respiration and increased lactate accumulation in the renal tissue. Consequently, these alterations will contribute to decrease the interstitial pO2, preferentially in the renal medulla of animals with sustained long-term hyperglycemia.

  • 50.
    Palm, Fredrik
    et al.
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Connors, Stephanie G
    Mendonca, Margarida
    Welch, William J
    Wilcox, Christopher S
    Angiotensin II Type 2 Receptors and Nitric Oxide Sustain Oxygenation in the Clipped Kidney of Early Goldblatt Hypertensive Rats2008In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 51, no 2, p. 345-351Article in journal (Refereed)
    Abstract [en]

    Angiotensin-converting enzyme inhibitors (ACEIs) decrease theglomerular filtration rate and renal blood flow in the clippedkidneys of early 2-kidney, 1-clip Goldblatt hypertensive rats,but the consequences for oxygenation are unclear. We investigatedthe hypothesis that angiotensin II type 1 or angiotensin IItype 2 receptors or NO synthase mediate renal oxygenation responsesto ACEI. Three weeks after left renal artery clipping, kidneyfunction, oxygen (O2) use, renal blood flow, renal corticalblood flow, and renal cortical oxygen tension (PO2) were measuredafter acute administration of an ACEI (enalaprilat) and afteracute administration of ACEI following acute administrationof an angiotensin II type 1 or angiotensin II type 2 receptorblocker (candesartan or PD-123,319) or an NO synthase blocker(NG-nitro-L-arginine methyl ester with control of renal perfusionpressure) and compared with mechanical reduction in renal perfusionpressure to the levels after ACEI. The basal renal corticalPO2 of clipped kidneys was significantly lower than contralateralkidneys (35±1 versus 51±1 mm Hg; n=40 each). ACEIlowered renal venous PO2, cortical PO2, renal blood flow, glomerularfiltration rate, and cortical blood flow and increased the renalvascular resistance in the clipped kidney, whereas mechanicalreduction in renal perfusion pressure was ineffective. PD-123,319and NG-nitro-L-arginine methyl ester, but not candesartan, reducedthe PO2 of clipped kidneys and blocked the fall in PO2 withacute ACEI administration. In conclusion, oxygen availabilityin the clipped kidney is maintained by angiotensin II generation,angiotensin II type 2 receptors, and NO synthase. This disclosesa novel mechanism whereby angiotensin can prevent hypoxia ina kidney challenged with a reduced perfusion pressure.

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