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Insulin induces the correlation between renal blood flow and glomerular filtration rate in diabetes: implications for mechanisms causing hyperfiltration
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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
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2012 (English)In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 303, no 1, R39-R47 p.Article in journal (Refereed) Published
Abstract [en]

Glomerular filtration rate (GFR) and renal blood flow (RBF) are normally kept constant via renal autoregulation. However, early diabetes results in increased GFR and the potential mechanisms are debated. Tubuloglomerular feedback (TGF) inactivation, with concomitantly increased RBF, is proposed but challenged by the finding of glomerular hyperfiltration in diabetic adenosine A(1) receptor-deficient mice, which lack TGF. Furthermore, we consistently find elevated GFR in diabetes with only minor changes in RBF. This may relate to the use of a lower streptozotocin dose, which produces a degree of hyperglycemia, which is manageable without supplemental suboptimal insulin administration, as has been used by other investigators. Therefore, we examined the relationship between RBF and GFR in diabetic rats with (diabetes + insulin) and without suboptimal insulin administration (untreated diabetes). As insulin can affect nitric oxide (NO) release, the role of NO was also investigated. GFR, RBF, and glomerular filtration pressures were measured. Dynamic RBF autoregulation was examined by transfer function analysis between arterial pressure and RBF. Both diabetic groups had increased GFR (+60-67%) and RBF (+20-23%) compared with controls. However, only the diabetes + insulin group displayed a correlation between GFR and RBF (R-2 = 0.81, P < 0.0001). Net filtration pressure was increased in untreated diabetes compared with both other groups. The difference between untreated and insulin-treated diabetic rats disappeared after administering N-omega-nitro-L-arginine methyl ester to inhibit NO synthase and subsequent NO release. In conclusion, mechanisms causing diabetes-induced glomerular hyperfiltration are animal model-dependent. Supplemental insulin administration results in a RBF-dependent mechanism, whereas elevated GFR in untreated diabetes is mediated primarily by a tubular event. Insulin-induced NO release partially contributes to these differences.

Place, publisher, year, edition, pages
2012. Vol. 303, no 1, R39-R47 p.
Keyword [en]
insulin, net filtraton pressure, N-omega-nitro-L-arginine methyl ester
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-179030DOI: 10.1152/ajpregu.00582.2011ISI: 000306186600005OAI: oai:DiVA.org:uu-179030DiVA: diva2:543084
Available from: 2012-08-06 Created: 2012-08-06 Last updated: 2017-12-07Bibliographically 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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 871
Keyword
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
Physiology
Research subject
Physiology; Medical Science
Identifiers
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)
Opponent
Supervisors
Available from: 2013-03-26 Created: 2013-03-01 Last updated: 2013-04-02Bibliographically approved

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Pihl, LiselottePersson, PatrikFasching, AngelicaHansell, PeterPalm, Fredrik

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