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

Significance Statement Increased sympathetic nerve activity plays an important role in hypertension and kidney disease. To investigate the role of α 2A-adrenergic receptors ( α 2A-adrenoceptors) in hypertension and hypertensive kidney disease, the authors induced angiotensin II (AngII)–dependent hypertension in wild-type and α 2A-adrenoceptor–knockout mice. Deletion of α 2A-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 α 2A-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 α 2A-adrenoceptors on sympathetic nerves, and α 2A-adrenoceptors act as autoreceptors by binding endogenous NE to inhibit its own release. However, the role of α 2A-adrenoceptors in the pathogenesis of hypertensive kidney disease is unknown. Methods We investigated effects of α 2A-adrenoceptor–regulated renal NE release on the development of angiotensin II–dependent hypertension and kidney disease. In uninephrectomized wild-type and α 2A-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 α 2A-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 α 2A-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 α 2A-adrenoceptor–knockout mice. Activation of specific sodium transporters accompanied the exaggerated hypertensive BP response in α 2A-adrenoceptor–deficient kidneys. These effects depend on renal nerves, as demonstrated by reduced severity of AngII-mediated hypertension and improved kidney function observed in α 2A-adrenoceptor–knockout mice after renal denervation. Conclusions Our findings reveal a protective role of prejunctional inhibitory α 2A-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.