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Diabetes-induced hyperfiltration in adenosine A(1)-receptor deficient mice lacking the tubuloglomerular feedback mechanism
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2007 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 190, no 3, 253-259 p.Article in journal (Refereed) Published
Abstract [en]

Aims: Glomerular hyperfiltration is commonly found in diabetic patients early after the onset of disease. This is one of the first indications of the development of progressive diabetic nephropathy. It has been proposed that glomerular hyperfiltration is caused by decreased delivery of electrolytes to the macula densa due to the increased sodium and glucose reabsorption in the proximal tubule, which would increase the glomerular filtration rate (GFR) via the tubuloglomerular feedback (TGF) mechanism. In this study, we investigated the role of TGF in diabetes-induced glomerular hyperfiltration by inducing diabetes in adenosine A1-receptor knockout (A1AR−/−) mice known to lack a functional TGF mechanism.

Methods: Diabetes was induced by alloxan (75 mg kg−1 bw) injected into the tail vein. The 24-hour urinary electrolyte excretion was measured in metabolic cages, the GFR determined by inulin clearance under isoflurane-anaesthesia, and histological changes evaluated.

Results: All alloxan-treated animals developed hyperglycaemia (≥20 mm). Normoglycaemic animals had a similar GFR independent of genotype (A1AR+/+ 9.3 ± 0.5 vs. A1AR−/− 10.1 ± 0.8 μL min−1g−1 bw) and diabetes resulted in similar glomerular hyperfiltration in both groups (A1AR+/+ 14.0 ± 1.7, n = 9 vs. A1AR−/− 15.3 ± 1.9 μL min−1g−1 bw). Diabetic animals had a similar tendency to develop interstitial fibrosis, whereas the glomerular volume was similar in both genotypes, and unaltered by diabetes.

Conclusions: This study shows that the A1AR−/− mice develop diabetes-induced glomerular hyperfiltration, demonstrating that the TGF mechanism is not the major cause of the development of hyperfiltration. Furthermore, the hyperfiltration in the present study was not related to alterations in the glomerular filtration area.

Place, publisher, year, edition, pages
2007. Vol. 190, no 3, 253-259 p.
Keyword [en]
adenosine, diabetes mellitus, glomerular hyperfiltration, tubuloglomerular feedback
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-11928DOI: 10.1111/j.1748-1716.2007.01705.xISI: 000247318600008PubMedID: 17581137OAI: oai:DiVA.org:uu-11928DiVA: diva2:39697
Available from: 2007-11-07 Created: 2007-11-07 Last updated: 2017-12-11Bibliographically 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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Sällström, JohanCarlsson, Per-OlaLarsson, ErikPersson, ErikPalm, Fredrik

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