α2A-Adrenoceptors Modulate Renal Sympathetic Neurotransmission and Protect against Hypertensive Kidney Disease

Abstract

BackgroundIncreased 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.MethodsWe 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.ResultsUrinary 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.ConclusionsOur 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.

Role of α2-Adrenoceptors in Hypertension: Focus on Renal Sympathetic Neurotransmitter Release, Inflammation, and Sodium Homeostasis

“…As shown in Figure 3, α1-adrenoceptors, α2-adrenoceptors, and β1-adrenergic receptors are expressed along the nephron (Dibona and Kopp, 1997;Lee et al, 2015;Sata et al, 2018;Kiuchi et al, 2019). During chronic Ang II infusion, sodium and volume excretion was significantly reduced in α2A-adrenoceptor deficient mice compared to wildtype mice (Hering et al, 2020). This impaired natriuretic response was in part caused by an increased abundance of the cleaved epithelial sodium channel (ENaC)-alpha and -gamma subtypes, both markers for ENaC activation (Nguyen et al, 2013;Veiras et al, 2020).…”

“…This α2-adrenoceptor activation modifies vascular tone, sodium handling, tubulo-interstitial fibrosis, and inflammation within the kidney (Starke et al, 1975;Gilsbach et al, 2009Gilsbach et al, , 2011Hoch et al, 2011;Kim and Padanilam, 2013;Jang et al, 2019;Hering et al, 2020; Figure 2). Although the effects of prejunctional released ATP and NPY are not the focus of this review, their effects on renal physiological and pathophysiological mechanisms are important.…”

“…RSNA affects natriuresis in several animal models and patients with resistant hypertension (Katayama et al, 2013;Poss et al, 2015;Hering et al, 2020). Renal sympathetic nerves also innervate renal tubules.…”

“…The role of α2-adrenoceptors in controlling natriuresis is still not fully understood, as it is hard to distinguish between α2-adrenoceptor-mediated effects and effects mediated by an increased renal sympathetic norepinephrine release. In general, it is widely accepted that increased sympathetic norepinephrine release increases ENaC expression and activation (Mansley et al, 2015;Hering et al, 2020). In contrast, renal denervation has been shown to reduce ENaC and aquaporin2 expression in a mouse model of heart failure, suggesting that the amount of renal norepinephrine release is relevant for the regulation of ENaC expression (Zheng et al, 2019).…”

“…Prejunctional α2-adrenoceptors serve as autoreceptors which, when activated by norepinephrine released from sympathetic nerve endings, inhibit the subsequent release of norepinephrine induced by a sympathetic nerve impulse (Figures 1, 2). Recent studies have highlighted the critical role of α2-adrenoceptors in the development of hypertension and kidney disease (Kim and Padanilam, 2013;Hering et al, 2020). However, α2-adrenergic receptors are not only expressed prejunctional on sympathetic nerves but also on non-adrenergic cells like immune cells, vascular smooth muscle cells (VSMCs), and renal epithelial cells.…”