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

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Item Type:	Article
Title:	α2A-adrenoceptors modulate renal sympathetic neurotransmission and protect against hypertensive kidney disease
Creators Name:	Hering, L., Rahman, M., Hoch, H., Markó, L., Yang, G., Reil, A., Yakoub, M., Gupta, V., Potthoff, S.A., Vonend, O., Ralph, D.L., Gurley, S.B., McDonough, A.A., 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
ISSN:	1046-6673
Publisher:	American Society of Nephrology
Volume:	31
Number:	4
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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