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Neuronal nitric oxide synthase supports renin release during sodium restriction through inhibition of phosphodiesterase 3
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi. (Erik Persson)
Physiology and Pharmacology, University of Southern Denmark.
Physiology and Pharmacology, University of Southern Denmark.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi. (Erik Persson)
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2010 (English)In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 23, no 11, 1241-1246 p.Article in journal (Refereed) Published
Abstract [en]

Background: Mice with targeted deletion of neuronal nitric oxide synthase (nNOS‑/‑) display inability to increase plasma renin concentration (PRC) in response to sodium restriction. nNOS has a distinct expression at the macula densa, and it has been hypothesized that nNOS supports renin release by cGMP-mediated inhibition of cAMP-specific phosphodiesterase 3 (PDE3) in juxtaglomerular cells.

Objective: To test the hypothesis that nNOS-derived NO supports renin release by inhibition of PDE3.

Methods: The experiments were performed in conscious nNOS-/- and wild types after ten days on a low sodium diet by acute treatment with the PDE3 inhibitor milrinone, the PDE5 inhibitor zaprinast, or vehicle, using a crossover study protocol. PRC was measured with the antibody-trapping technique and blood pressure with telemetry. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were estimated by measurements of inulin- and Para-Amino Hippuric acid clearances, respectively.

Results: The basal PRC was reduced in nNOS-/- compared to the wild types. Administration of milrinone caused a more pronounced PRC increase in nNOS-/-, resulting in normalized renin levels, while PDE5 inhibition did not affect PRC in any genotype. The blood pressure was similar in both genotypes, and milrinone did not affect blood pressure compared to vehicle. GFR and RPF were similar at baseline and were reduced by milrinone.

Conclusions: The present study provides in vivo evidence supporting the view that NO, selectively derived from nNOS, mediates renin release during sodium restriction by inhibiting PDE3, which would increase renin release by elevating cAMP levels in the juxtaglomerular cells.

Place, publisher, year, edition, pages
2010. Vol. 23, no 11, 1241-1246 p.
National Category
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-113177DOI: 10.1038/ajh.2010.153ISI: 000283531900016OAI: oai:DiVA.org:uu-113177DiVA: diva2:290077
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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