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α2A-adrenoceptors modulate renal sympathetic neurotransmission and protect against hypertensive kidney disease

Item Type:Article
Title:α2A-adrenoceptors modulate renal sympathetic neurotransmission and protect against hypertensive kidney disease
Creators Name:Hering, L. and Rahman, M. and Hoch, H. and Markó, L. and Yang, G. and Reil, A. and Yakoub, M. and Gupta, V. and Potthoff, S.A. and Vonend, O. and Ralph, D.L. and Gurley, S.B. and McDonough, A.A. and Rump, L.C. and Stegbauer, J.
Abstract:BACKGROUND: Increased nerve activity causes hypertension and kidney disease. Recent studies suggest that renal denervation reduces BP in patients with hypertension. Renal NE release is regulated by prejunctional α2A-adrenoceptors on sympathetic nerves, and α2A-adrenoceptors act as autoreceptors by binding endogenous NE to inhibit its own release. However, the role of α2A-adrenoceptors in the pathogenesis of hypertensive kidney disease is unknown. METHODS: We investigated effects of α2A-adrenoceptor-regulated renal NE release on the development of angiotensin II-dependent hypertension and kidney disease. In uninephrectomized wild-type and α2A-adrenoceptor-knockout mice, we induced hypertensive kidney disease by infusing AngII for 28 days. RESULTS: Urinary NE excretion and BP did not differ between normotensive α2A-adrenoceptor-knockout mice and wild-type mice at baseline. However, NE excretion increased during AngII treatment, with the knockout mice displaying NE levels that were significantly higher than those of wild-type mice. Accordingly, the α2A-adrenoceptor-knockout mice exhibited a systolic BP increase, which was about 40 mm Hg higher than that found in wild-type mice, and more extensive kidney damage. In isolated kidneys, AngII-enhanced renal nerve stimulation induced NE release and pressor responses to a greater extent in kidneys from α2A-adrenoceptor-knockout mice. Activation of specific sodium transporters accompanied the exaggerated hypertensive BP response in α2A-adrenoceptor-deficient kidneys. These effects depend on renal nerves, as demonstrated by reduced severity of AngII-mediated hypertension and improved kidney function observed in α2A-adrenoceptor-knockout mice after renal denervation. CONCLUSIONS: Our findings reveal a protective role of prejunctional inhibitory α2A-adrenoceptors in pathophysiologic conditions with an activated renin-angiotensin system, such as hypertensive kidney disease, and support the concept of sympatholytic therapy as a treatment.
Keywords:Angiotensin, Chronic Kidney Disease, Epithelial Sodium Transport, Hypertension, Renal Sympathetic Nervous System, α2-Adrenoceptor, Animals, Mice
Source:Journal of the American Society of Nephrology
Publisher:American Society of Nephrology
Page Range:783-798
Date:April 2020
Additional Information:Copyright © 2020 by the American Society of Nephrology
Official Publication:https://doi.org/10.1681/ASN.2019060599
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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