α2A-Adrenoceptors Modulate Renal Sympathetic Neurotransmission and Protect against Hypertensive Kidney Disease
Authors: Hering Lydia , Rahman Masudur , Hoch Henning , Markó Lajos , Yang Guang , Reil Annika , Yakoub Mina , Gupta Vikram , Potthoff Sebastian A. , Vonend Oliver , Ralph Donna L. , Gurley Susan B. , McDonough Alicia A. , Rump Lars C. , Stegbauer Johannes 
Published: February 2020

Significance Statement

Increased sympathetic nerve activity plays an important role in hypertension and kidney disease. To investigate the role of α2A-adrenergic receptors (α2A-adrenoceptors) in hypertension and hypertensive kidney disease, the authors induced angiotensin II (AngII)–dependent hypertension in wild-type and α2A-adrenoceptor–knockout mice. Deletion of α2A-adrenoceptors increased AngII-facilitated renal NE release and activated specific sodium transporters within the kidney. During AngII treatment, knockout mice had significantly higher systolic BP and heightened kidney damage compared with wild-type mice. Renal denervation attenuated AngII-dependent hypertension and improved renal function in knockout mice. These findings show that α2A-adrenoceptors are important regulators of renal sympathetic outflow in hypertension and protect from hypertensive kidney disease, and support the concept that reducing renal sympathetic nerve activity holds promise as a therapeutic approach for hypertension and hypertensive kidney disease.

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.