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  • 1.
    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.

  • 2.
    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.

  • 3. 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.

  • 4.
    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.

  • 5.
    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)
  • 6.
    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.

  • 7.
    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.

  • 8.
    Palm, Fredrik
    et al.
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Nangaku, Masaomi
    Fasching, Angelica
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Tanaka, Tetsuhiro
    Nordquist, Lina
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Hansell, Peter
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Kawakami, Takahisa
    Nishijima, Fuyuhiko
    Fujita, Toshiro
    Uremia induces abnormal oxygen consumption in tubules and aggravates chronic hypoxia of the kidney via oxidative stress2010In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 299, no 2, p. F380-F386Article in journal (Refereed)
    Abstract [en]

    In addition to causing uremic symptoms, uremic toxins accelerate the progression of renal failure. To elucidate the pathophysiology of uremic states, we investigated the effect of indoxyl sulfate (IS), a representative uremic toxin, on oxygen metabolism in tubular cells. We demonstrated an increase in oxygen consumption by IS in freshly isolated rat and human proximal tubules. Studies utilizing ouabain, the Na-K-ATPase inhibitor, and apocynin, the NADPH oxidase inhibitor, as well as the in vivo gene-silencing approach to knock down p22(phox) showed that the increase in tubular oxygen consumption by IS is dependent on Na-K-ATPase and oxidative stress. We investigated whether the enhanced oxygen consumption led to subsequent hypoxia of the kidney. An increase in serum IS concentrations in rats administered indole was associated with a decrease in renal oxygenation (8 h). The remnant kidney in rats developed hypoxia at 16 wk. Treatment of the rats with AST-120, an oral adsorbent that removes uremic toxins, reduced serum IS levels and improved oxygenation of the kidney. Amelioration of hypoxia in the remnant kidney was associated with better renal functions and less histological injury. Reduction of serum IS levels also led to a decrease in oxidative stress in the kidney. Our ex vivo and in vivo studies implicated that uremic states may deteriorate renal dysfunction via dysregulating oxygen metabolism in tubular cells. The abnormal oxygen metabolism in tubular cells by uremic toxins was, at least in part, mediated by oxidative stress.

  • 9.
    Palm, Fredrik
    et al.
    Uppsala universitet, Integrativ Fysiologi.
    Nordquist, Lina
    Uppsala universitet, Integrativ Fysiologi.
    Renal oxidative stress, oxygenation and hypertension2011In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 301, no 5, p. R1229-R1241Article in journal (Refereed)
    Abstract [en]

    Hypertension is closely associated with progressive kidney dysfunction, manifested as glomerulosclerosis, interstitial fibrosis, proteinuria and eventually declining glomerular filtration. The postulated mechanism for development of glomerulosclerosis is barotrauma caused by increased capillary pressure, but the reason for development of interstitial fibrosis and the subsequently reduced kidney function is less clear. However, it has been hypothesized that tissue hypoxia induces fibrogenesis and progressive renal failure. This is very interesting, since recent reports highlight several different mechanisms resulting in altered oxygen handling and availability in the hypertensive kidney. Such mechanisms include decreased renal blood flow due to increased vascular tone induced by angiotensin II that limits oxygen delivery, increased oxidative stress resulting in increased mitochondrial oxygen usage, increased oxygen usage for tubular electrolyte transport and shunting of oxygen from arterial to venous blood in preglomerular vessels. It has been shown in several studies that interventions to prevent oxidative stress and to restore kidney tissue oxygenation prevent progression of kidney dysfunction. Furthermore, inhibition of angiotensin II activity, by either blocking AT(1)-receptors or angiotensin converting enzyme, or by preventing oxidative stress by administration of antioxidants also results in improved blood pressure control. It therefore seems likely that tissue hypoxia in the hypertensive kidney contributes to progression of kidney damage and perhaps also maintaining the high blood pressure.

  • 10.
    Palm, Fredrik
    et al.
    Uppsala universitet, Integrativ Fysiologi.
    Nordquist, Lina
    Uppsala universitet, Integrativ Fysiologi.
    Renal tubulointerstitial hypoxia: Cause and consequence of kidney dysfunction2011In: Clinical and experimental pharmacology & physiology, ISSN 0305-1870, E-ISSN 1440-1681, Vol. 38, no 7, p. 424-430Article in journal (Refereed)
    Abstract [en]

    1. Intrarenal oxygen availability is the balance between supply, mainly dependent on renal blood flow, and demand, determined by the basal metabolic demand and the energy-requiring tubular electrolyte transport. Renal blood flow is maintained within close limits in order to sustain stable glomerular filtration, so increased intrarenal oxygen consumption is likely to cause tissue hypoxia.

    2. The increased oxygen consumption is closely linked to increased oxidative stress, which increases mitochondrial oxygen usage and reduces tubular electrolyte transport efficiency, with both contributing to increased total oxygen consumption.

    3. Tubulointerstitial hypoxia stimulates the production of collagen I and alpha-smooth muscle actin, indicators of increased fibrogenesis. Furthermore, the hypoxic environment induces epithelial-mesenchymal transdifferentiation and aggravates fibrosis, which results in reduced peritubular blood perfusion and oxygen delivery due to capillary rarefaction.

    4. Increased oxygen consumption, capillary rarefaction and increased diffusion distance due to the increased fibrosis per se further aggravate the interstitial hypoxia.

    5. Recently, it has been demonstrated that hypoxia simulates the infiltration and maturation of immune cells, which provides an explanation for the general inflammation commonly associated with the progression of chronic kidney disease. 6. Therapies targeting interstitial hypoxia could potentially reduce the progression of chronic renal failure in millions of patients who are otherwise likely to eventually present with fully developed end-stage renal disease.

  • 11.
    Palm, Fredrik
    et al.
    Uppsala universitet, Integrativ Fysiologi.
    Nordquist, Lina
    Uppsala universitet, Integrativ Fysiologi.
    Buerk, Donald G.
    Nitric oxide in the kidney: Direct measurements of bioavailable renal nitric oxide2008In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 599, p. 117-123Article in journal (Refereed)
    Abstract [en]

    Increasing efforts have been directed towards investigating the involvement of nitric oxide (NO) for normal kidney function. Recently, a crucial role of NO in the development of progressive renal dysfunction has been reported during diabetes and hypertension. Indirect estimation of renal NO production include urinary nitrite/nitrate measurements, but there are several disadvantages of indirect methods since production and bioavailability of NO rarely coincide. Thus, direct measurement of in vivo NO bioavailability is preferred, although these methods are more time consuming and require highly specialized equipment and knowledge. This review focuses on two techniques for in vivo measurement of bioavailable NO in the kidney. We have applied Whalen-type recessed NO microsensors for measurement of NO in the kidney cortex, whereas the hemoglobin-trapping technique seems to be more suitable for NO measurement in the renal medulla. Both methods are robust and reliable, and we discuss advantages and shortcomings of each method.

  • 12.
    Stridh, Sara
    et al.
    Uppsala universitet, Integrativ Fysiologi.
    Sällström, Johan
    Uppsala universitet, Integrativ Fysiologi.
    Fridén, Markus
    Uppsala universitet, Institutionen för farmaceutisk biovetenskap.
    Hansell, Peter
    Uppsala universitet, Integrativ Fysiologi.
    Nordquist, Lina
    Uppsala universitet, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Integrativ Fysiologi.
    C-peptide normalizes glomerular filtration rate in hyperfiltrating conscious diabetic rats2009In: Oxygen transport to tissue xxx / [ed] Per Liss, New York: Springer , 2009, p. 219-225Chapter in book (Refereed)
    Abstract [en]

    Tubular electrolyte transport accounts for a major part of the oxygen consumed by the normal kidney. We have previously reported a close association between diabetes and increased oxygen usage, partly due to increased tubular electrolyte transport secondary to glomerular hyperfiltration during the early onset of diabetes. Several studies have shown that acute administration of C-peptide to diabetic rats with glomerular hyperfiltration results in normalized glomerular filtration rate (GFR). In this study, we validated a novel method for precise and repetitive GFR measurements in conscious rats and used C-peptide injection in diabetic rats for evaluation. First, GFR was determined in normoglycemic control rats before and after C-peptide administration. Thereafter, all rats were made diabetic by an i.v. streptozotocin injection. Fourteen days later, GFR was again determined before and after C-peptide administration. GFR was estimated from plasma clearance curves using a single bolus injection of FITC-inulin, followed by serial blood sampling over 155 min. FITC-inulin clearance was calculated using non-compartmental pharmacokinetic data analysis. Baseline GFR in normoglycemic controls was 2.10 +/- 0.18 ml/min, and was unaffected by C-peptide (2.23 +/- 0.14 ml/min). Diabetic rats had elevated GFR (3.06 +/- .034 ml/min), which was normalized by C-peptide (2.35 +/- 0.30 ml/min). In conclusion, the used method for estimation of GFR in conscious animals result in values that are in good agreement with those obtained from traditional GFR measurements on anaesthetized rats. However, multiple measurements from the same conscious subject can be obtained using this method. Furthermore, as previously shown on anaesthetized rats, C-peptide also normalizes GFR in hyperfiltrating conscious diabetic rats.

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