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Chronic treatment with angiotensin-(1-7) improves renal endothelial dysfunction in apolipoproteinE-deficient mice
Authors:Stegbauer J  Potthoff S A  Quack I  Mergia E  Clasen T  Friedrich S  Vonend O  Woznowski M  Königshausen E  Sellin L  Rump L C
Affiliation:1Department of Nephrology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany;2Department of Pharmacology and Toxicology, Medical Faculty MA N1, Ruhr-University Bochum, Bochum, Germany
Abstract:

BACKGROUND AND PURPOSE

ApolipoproteinE-deficient [apoE (−/−)] mice, a model of human atherosclerosis, develop endothelial dysfunction caused by decreased levels of nitric oxide (NO). The endogenous peptide, angiotensin-(1-7) [Ang-(1-7)], acting through its specific GPCR, the Mas receptor, has endothelium-dependent vasodilator properties. Here we have investigated if chronic treatment with Ang-(1-7) improved endothelial dysfunction in apoE (−/−) mice.

EXPERIMENTAL APPROACH

ApoE (−/−) mice fed on a lipid-rich Western diet were divided into three groups and treated via osmotic minipumps with either saline, Ang-(1-7) (82 µg·kg−1·h−1) or the same dose of Ang-(1-7) together with D-Ala-Ang-(1-7) (125 µg·kg−1·h−1) for 6 weeks. Renal vascular function was assessed in isolated perfused kidneys.

KEY RESULTS

Ang-(1-7)-treated apoE (−/−) mice showed improved renal endothelium-dependent vasorelaxation induced by carbachol and increased renal basal cGMP production, compared with untreated apoE (−/−) mice. Tempol, a reactive oxygen species (ROS) scavenger, improved endothelium-dependent vasorelaxation in kidneys of saline-treated apoE (−/−) mice whereas no effect was observed in Ang-(1-7)-treated mice. Chronic treatment with D-Ala-Ang-(1-7), a specific Mas receptor antagonist, abolished the beneficial effects of Ang-(1-7) on endothelium-dependent vasorelaxation. Renal endothelium-independent vasorelaxation showed no differences between treated and untreated mice. ROS production and expression levels of the NAD(P)H oxidase subunits gp91phox and p47phox were reduced in isolated preglomerular arterioles of Ang-(1-7)-treated mice, compared with untreated mice, whereas eNOS expression was increased.

CONCLUSION AND IMPLICATIONS

Chronic infusion of Ang-(1-7) improved renal endothelial function via Mas receptors, in an experimental model of human cardiovascular disease, by increasing levels of endogenous NO.
Keywords:endothelial dysfunction   angiotensin II   angiotensin-(1-7)   NO bioavailability   reactive oxygen species   apolipoproteinE knockout mouse
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