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Adenosine A2 receptor-mediated regulation of renal hemodynamics and glomerular filtration rate is abolished in diabetes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
2013 (English)In: Oxygen Transport to Tissue XXXIV, Springer-Verlag New York, 2013, Vol. 765, 225-230 p.Chapter in book (Refereed)
Abstract [en]

Alterations in glomerular filtration rate (GFR) are one of the earliest indications of altered kidney function in diabetes. Adenosine regulates GFR through tubuloglomerular feedback mechanism acting on adenosine A1 receptor. In addition, adenosine can directly regulate vascular tone by acting on A1 and A2 receptors expressed in afferent and efferent arterioles. Opposite to A1 receptors, A2 receptors mediate vasorelaxation. This study investigates the involvement of adenosine A2 receptors in regulation of renal blood flow (RBF) and GFR in control and diabetic kidneys. GFR was measured by inulin clearance and RBF by a transonic flow probe placed around the renal artery. Measurements were performed in isoflurane-anesthetized normoglycemic and alloxan-diabetic C57BL/6 mice during baseline and after acute administration of 3,7-dimethyl-1-propargylxanthine (DMPX), a selective A2 receptor antagonist. GFR and RBF were lower in diabetic mice compared to control (258 ± 61 vs. 443 ± 33 μl min -1 and 1,083 ± 51 vs. 1,405 ± 78 μl min -1). In control animals, DMPX decreased RBF by-6%, whereas GFR increased +44%. DMPX had no effects on GFR and RBF in diabetic mice. Sodium excretion increased in diabetic mice after A2 receptor blockade (+78%). In conclusion, adenosine acting on A2 receptors mediates an efferent arteriolar dilatation which reduces filtration fraction (FF) and maintains GFR within normal range in normoglycemic mice. However, this regulation is absent in diabetic mice, which may contribute to reduced oxygen availability in the diabetic kidney.

Place, publisher, year, edition, pages
Springer-Verlag New York, 2013. Vol. 765, 225-230 p.
, Advances in Experimental Medicine and Biology, ISSN 0065-2598 ; 765
Keyword [en]
Alloxan, C57BL/6, DMPX, Renal blood flow
National Category
Medical and Health Sciences Basic Medicine
URN: urn:nbn:se:uu:diva-186810DOI: 10.1007/978-1-4614-4989-8_31ISI: 000339280100032ISBN: 9781461447719OAI: oai:DiVA.org:uu-186810DiVA: diva2:576090
Available from: 2012-12-12 Created: 2012-11-29 Last updated: 2014-08-26Bibliographically approved
In thesis
1. Aspects of Regulation of GFR and Tubular Function in the Diabetic Kidney: Roles of Adenosine, Nitric Oxide and Oxidative Stress
Open this publication in new window or tab >>Aspects of Regulation of GFR and Tubular Function in the Diabetic Kidney: Roles of Adenosine, Nitric Oxide and Oxidative Stress
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diabetic nephropathy is the main cause for initiation of renal replacement therapy and early symptoms in patients include increased glomerular filtration rate (GFR), decreased oxygen tension and albuminuria, followed by a progressive decline in GFR and loss of kidney function. Experimental models of diabetes display increased GFR, decreased tissue oxygenation and nitric oxide bioavailability. These findings are likely to be intertwined in a mechanistic pathway to kidney damage and this thesis investigated their roles in the development of diabetic nephropathy. In vivo, diabetes-induced oxidative stress stimulates renal tubular Na+ transport and in vitro, proximal tubular cells from diabetic rats display increased transport-dependent oxygen consumption, demonstrating mechanisms contributing to decreased kidney oxygenation. In control animals, endogenous adenosine reduces vascular resistance of the efferent arteriole via adenosine A2-receptors resulting in reduced filtration fraction. However, in diabetes, adenosine A2-signalling is dysfunctional resulting in increased GFR via increased filtration fraction. This is caused by reduced adenosine A2a receptor-mediated vasodilation of efferent arterioles. The lack of adenosine-signaling in diabetes is likely due to reduced local adenosine concentration since adenosine A2a receptor activation reduced GFR only in diabetic animals by efferent arteriolar vasodilation. Furthermore, sub-optimal insulin treatment also alleviates increased filtration pressure in diabetes. However, this does not affect GFR due to a simultaneously induction of renal-blood flow dependent regulation of GFR by increasing the filtration coefficient. In diabetes, there is decreased bioavailability of nitric oxide, resulting in alterations that may contribute to diabetes-induced hyperfiltration and decreased oxygenation. Interestingly, increased plasma concentration of l-arginine, the substrate for nitric oxide production, prevents the development of increased GFR and proteinuria, but not increased oxygen consumption leading to sustained intra-renal hypoxia in diabetes. This thesis concludes that antioxidant treatment directed towards the NADPH oxidase as well maneuvers to promote nitric oxide production is beneficial in diabetic kidneys but is targeting different pathways i.e. transport-dependent oxygen consumption in the proximal tubule by NADPH oxidase inhibition and intra-renal hemodynamics after increased plasma l-arginine. Also, the involvement and importance of efferent arteriolar resistance in the development of diabetes-induced hyperfiltration via reduced adenosine A2a signaling is highlighted.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 54 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 871
diabetes, diabetic nephropathy, glomerular filtration rate, renal blood flow, insulin, renal hemodynamics, micropuncture, oxygen, NADPH-oxidase, apocynin, streptozotocin, l-arginine, CGS21680, rats, mice
National Category
Research subject
Physiology; Medical Science
urn:nbn:se:uu:diva-195956 (URN)978-91-554-8610-5 (ISBN)
Public defence
2013-04-19, A1:107a, BMC, Husargatan 3, Uppsala, 09:15 (Swedish)
Available from: 2013-03-26 Created: 2013-03-01 Last updated: 2013-04-02Bibliographically approved

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Persson, PatrikHansell, PeterPalm, Fredrik
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