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Inhibition of sodium-linked glucose reabsorption in the kidney normalizes diabetes-induced glomerular hyperfiltration in conscious adenosine A1-receptor-deficient mice
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. (Erik Persson)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. (Erik Persson)
Fysiologi och Farmakologi, Karolinska Institutet.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. (Erik Persson)
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2014 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 210, no 2, 440-445 p.Article in journal (Refereed) Published
Abstract [en]

Glomerular hyperfiltration is commonly observed in diabetics early after the onset of the disease and predicts the progression of nephropathy. In this study, we investigated the role of the increased tubular sodium/glucose co-transport for diabetes-induced glomerular hyperfiltration. To eliminate any potential confounding effect of the tubuloglomerular feedback mechanism (TGF), we used adenosine A1-receptor deficient (A1AR-/-) mice known to lack a functional TGF mechanism, and compared the results to corresponding wild-type animals (A1AR+/+). Diabetes was induced by an intravenous bolus injection of alloxan. Glomerular filtration rate (GFR) was determined in conscious mice by a single bolus injection of inulin. The sodium/glucose co-transporters were inhibited by phlorizin 30 minutes prior to GFR measurements. Normoglycemic animals had a similar GFR independent of genotype, and induction of diabetes resulted in similar glomerular hyperfiltration in both groups. Phlorizin had no effect on GFR in normoglycemic mice, whereas it reduced GFR in both genotypes during diabetes. Notably, the reduction was more pronounced in the A1AR-/-. This study demonstrates that increased tubular sodium/glucose reabsorption is important for diabetes-induced hyperfiltration, and that the TGF mechanism is not involved in these alterations, but rather functions to reduce any deviations from a new set-point.

Place, publisher, year, edition, pages
2014. Vol. 210, no 2, 440-445 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-113176DOI: 10.1111/apha.12152ISI: 000329519500020OAI: oai:DiVA.org:uu-113176DiVA: diva2:290076
Available from: 2010-01-26 Created: 2010-01-26 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Functional Aspects of the Juxtaglomerular Apparatus: Control of Glomerular Filtration and Renin Release
Open this publication in new window or tab >>Functional Aspects of the Juxtaglomerular Apparatus: Control of Glomerular Filtration and Renin Release
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The juxtaglomerular apparatus (JGA) is a control unit of the kidney, that regulates glomerular filtration rate (GFR) and renin release, and hence extracellular volume and blood pressure. The tubuloglomerular feedback (TGF) mechanism is a negative feedback loop that regulates GFR. Neuronal nitric oxide synthase (nNOS) is highly expressed in the macula densa cells of the JGA, and regulates the sensitivity of the TGF mechanism. Hypertension has been proposed to be caused by an increased sensitivity of the TGF due to nNOS deficiency. In diabetes, reduced TGF activity due to increased sodium-glucose reabsorption is suggested to cause hyperfiltration. Glomerular hyperfiltration has clinical significance, since it correlates with the risk of developing nephropathy.

In this thesis, the role of nNOS in the control of blood pressure and renin release was investigated in nNOS knockout mice (nNOS-/-) treated with low- and high sodium diets. The nNOS-/- were normotensive, but displayed an impaired renin regulation, and failed to increase renin in response to a low sodium diet. A significantly larger renin increase during phosphodiesterase 3 (PDE3) inhibition was found in nNOS-/- compared to the wild types, resulting in similar renin levels.

Furthermore, the role of TGF and proximal glucose reabsorption in diabetes-induced hyperfiltration was investigated in adenosine A1-receptor knockout mice (A1AR-/-) that are known to lack a functional TGF mechanism. Diabetes was induced in A1AR-/- and wild types by injection of alloxan. The diabetic A1AR-/- displayed a similar degree of hyperfiltration as their wild-type controls. Inhibition of renal sodium-glucose transporters reduced GFR in both genotypes, but the reduction was even more pronounced in the A1AR-/-.

In conclusion, the results indicate that renin secretion during low sodium conditions is mediated by nNOS-derived nitric oxide via cGMP-mediated inhibition of PDE3, whereas deletion of the nNOS gene does not cause hypertension. Diabetes-induced hyperfiltration is not mediated by TGF, but appears to be dependent on increased renal glucose reabsorption.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 71 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 518
National Category
Medical and Health Sciences
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-113178 (URN)978-91-554-7715-8 (ISBN)
Public defence
2010-03-10, B22, BMC, Husargatan 3, Uppsala, 13:15 (English)
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Supervisors
Available from: 2010-02-17 Created: 2010-01-26 Last updated: 2010-02-17Bibliographically approved

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