<i>α</i>2A-Adrenoceptors Modulate Renal Sympathetic Neurotransmission and Protect against Hypertensive Kidney Disease.

Abstract

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 <i>α</i>2A-adrenoceptors on sympathetic nerves, and <i>α</i>2A-adrenoceptors act as autoreceptors by binding endogenous NE to inhibit its own release. However, the role of <i>α</i>2A-adrenoceptors in the pathogenesis of hypertensive kidney disease is unknown. We investigated effects of <i>α</i>2A-adrenoceptor-regulated renal NE release on the development of angiotensin II-dependent hypertension and kidney disease. In uninephrectomized wild-type and <i>α</i>2A-adrenoceptor-knockout mice, we induced hypertensive kidney disease by infusing AngII for 28 days. Urinary NE excretion and BP did not differ between normotensive <i>α</i>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 <i>α</i>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 <i>α</i>2A-adrenoceptor-knockout mice. Activation of specific sodium transporters accompanied the exaggerated hypertensive BP response in <i>α</i>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 <i>α</i>2A-adrenoceptor-knockout mice after renal denervation. Our findings reveal a protective role of prejunctional inhibitory <i>α</i>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.