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Intrarenal activation of endothelin type B receptors improve intrarenal oxygenation in type 1 diabetic rats
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Center for Medical Image Science and Visualization (CMIV). (Experimentell Njurmedicin)
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Center for Medical Image Science and Visualization (CMIV).
(English)Manuscript (preprint) (Other academic)
Keyword [en]
nephropathy, diabetes, hypoxia, endothelin, sarafotoxin 6c
National Category
URN: urn:nbn:se:liu:diva-125525OAI: diva2:906768

About one third of patients with type 1 diabetes develop kidney damage. The mechanism is largely unknown, but intrarenal hypoxia has been proposed as a unifying mechanism for chronic kidney disease including diabetic nephropathy. The endothelin system has recently been demonstrated to regulate oxygen availability in the diabetic kidney via a pathway involving endothelin type A receptors (ETA-R). These receptors mainly mediate vasoconstriction and tubular sodium retention, and inhibition of ETA-R improves intrarenal oxygenation in the diabetic kidney. Endothelin type B receptors (ETB-R) have been reported to have opposite effects on vascular tone and tubular sodium handling. However, the role of ETB-R in kidney oxygen homeostasis is unknown.

The effects of acute intrarenal ETB-R activation (Sarafotoxin 6c for 30-40 minutes; 0.78 pmol h-1 directly into the renal artery) on kidney function and oxygen metabolism were investigated in normoglycemic control and insulinopenic male Sprague Dawley rats administered streptozotocin (55 mg kg-1) two weeks before the acute experiments.

Intrarenal activation of ETB-R improved oxygenation of the hypoxia diabetic kidney. However, neither effects on the diabetes-induced increased kidney oxygen consumption nor alterations in parameters related to tubular sodium transport could explain the improved oxygenation in the diabetic kidney after ETB-R activation. Rather, the improved kidney oxygenation was due to hemodynamic effects increasing oxygen delivery.

In conclusion, increased ETB-R signaling in the diabetic kidney improves tissue oxygenation due to increased oxygen delivery as a result of increased total renal blood flow.

Available from: 2016-02-25 Created: 2016-02-25 Last updated: 2016-03-09
In thesis
1. The role of hypoxia for the development of diabetic nephropathy: Temporal relationship and involvement of endothelin receptor signaling
Open this publication in new window or tab >>The role of hypoxia for the development of diabetic nephropathy: Temporal relationship and involvement of endothelin receptor signaling
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diabetic nephropathy is one of the most common causes of end stage renal disease and develops in approximately one third of all diabetes patients. Disease progression is characterized by deteriorating glomerular filtration rate and escalating urinary albumin/protein excretion; both are used as clinical markers for disease progression. Recently, it has been proposed that intrarenal hypoxia is a unifying mechanism for chronic kidney disease, including diabetic nephropathy. Several mechanistic pathways have been linked to the development of intrarenal hypoxia and diabetic nephropathy including increased angiotensin II signaling, oxidative stress and hyperglycemia per se. Furthermore, pathological endothelin signaling has recently immerged as a possible contributing factor for chronic kidney disease and diabetic nephropathy. The overall aims of this thesis were therefore to determine the temporal relationship between development of intrarenal hypoxia and kidney disease as well as elucidate the potential link between endothelin signaling, intrarenal hypoxia and kidney disease in experimental insulinopenic diabetes.

It is well established that different mouse strains have different susceptibility for kidney and cardiovascular disease. The first step was therefore to compare four commonly used mouse strains with regards to development of kidney disease after onset of insulinopenic diabetes. From the results of this study, we concluded that the NMRI mouse strain has a disease progression closest to the human disease and this strain was chosen in the subsequent studies in mice.

The next step was to adapt and optimize a suitable method for repetitive measurements of intrarenal oxygen tension during the course of disease development. Electron paramagnetic resonance (EPR) oximetry had previously been used in tumor biology and was now adapted and optimized for measurements of kidney oxygenation in our diabetic mouse model. EPR oximetry in normoglycemic control mice recorded cortical oxygen tension values similar to previous reports using invasive techniques. Surprisingly, intrarenal hypoxia developed already within the first 72h after induction of hyperglycemia and persisted throughout the two-week study period. Importantly, this was well before albuminuria developed.

The final part of this thesis was to investigate the role of endothelin signaling for the intrarenal hypoxia in a diabetic rat model. Endothelin 1 signals via two distinctly different receptor-mediated pathways. In normal physiology, endothelin 1 binding to endothelin receptor type A (ETA) induces vasoconstriction, which can be blocked by the specific ETA antagonist BQ123, whereas endothelin 1 binding to endothelin receptor type B (ETB) induces nitric oxide-dependent vasodilation. ETB receptors can be selectively activated by Sarafotoxin 6c. The results from blocking ETA and activating ETB receptors demonstrated that endothelin 1 signaling via ETA receptors contributes to intrarenal hypoxia in the rat diabetic kidney, and that ETB stimulation significantly reduces the diabetes-induced intrarenal hypoxia. The beneficial effects on kidney oxygen availability in diabetes by ETA blockade or ETB stimulation were mainly linked to hemodynamic improvements rather than direct effects on kidney oxygen consumption or oxidative stress status.

In conclusion, by applying EPR oximetry in a mouse model of insulinopenic diabetes mimicking the human disease, we demonstrated intrarenal hypoxia already within the first couple of days after the onset of hyperglycemia, which is well before detectable signs of kidney disease development. Furthermore, blockade of ETA or activation of ETB receptors significantly reduced intrarenal hypoxia in the diabetic kidney. These results demonstrate involvement of ETA receptor signaling in diabetes-induced intrarenal hypoxia and ETA blockade or ETB activation might provide new therapeutical targets to reduce kidney hypoxia and disease progression in diabetes.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. 53 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1510
nephropathy, diabetes, hypoxia, EPR
National Category
urn:nbn:se:liu:diva-125522 (URN)10.3384/diss.diva-125522 (DOI)978-91-7685-825-7 (Print) (ISBN)
Public defence
2016-04-29, Berzelius, Campus US, Linköping, 13:00 (English)
Swedish Heart Lung FoundationSwedish Research CouncilSwedish Diabetes Association
Available from: 2016-03-09 Created: 2016-02-25 Last updated: 2016-03-09Bibliographically approved

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