Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney

Abstract

Essential hypertension is a common disease, yet its pathogenesis is not well understood. Altered control of sodium excretion in the kidney may be a key causative feature, but this has been difficult to test experimentally, and recent studies have challenged this hypothesis. Based on the critical role of the renin-angiotensin system (RAS) and the type I (AT 1) angiotensin receptor in essential hypertension, we developed an experimental model to separate AT 1 receptor pools in the kidney from those in all other tissues. Although actions of the RAS in a variety of target organs have the potential to promote high blood pressure and end-organ damage, we show here that angiotensin II causes hypertension primarily through effects on AT 1 receptors in the kidney. We find that renal AT1 receptors are absolutely required for the development of angiotensin II-dependent hypertension and cardiac hypertrophy. When AT 1 receptors are eliminated from the kidney, the residual repertoire of systemic, extrarenal AT1 receptors is not sufficient to induce hypertension or cardiac hypertrophy. Our findings demonstrate the critical role of the kidney in the pathogenesis of hypertension and its cardiovascular complications. Further, they suggest that the major mechanism of action of RAS inhibitors in hypertension is attenuation of angiotensin II effects in the kidney. transgenic mice ͉ kidney transplantation ͉ blood pressure H igh blood pressure (BP) is a highly prevalent disorder, and its complications (including heart disease, stroke, and kidney disease) are a major public health problem (1). Despite decades of scrutiny, the precise pathogenesis of essential hypertension has been difficult to delineate. Guyton and his associates suggested that defective handling of sodium by the kidney and consequent dysregulation of body fluid volumes is a requisite, final common pathway in hypertension pathogenesis (2). The powerful capacity of this pathway to modulate blood pressure is illustrated by the elegant studies of Lifton and associates showing that virtually all of the Mendelian disorders with major impact on blood pressure homeostasis are caused by genetic variants affecting salt and water reabsorption by the distal nephron (3). On the other hand, several recent studies have suggested that primary vascular defects may cause hypertension by impacting peripheral resistance without direct involvement of renal excretory functions (4-7).Among the various regulatory systems that impact blood pressure, the RAS has a key role. Inappropriate activation of the RAS, as in renal artery stenosis, leads to profound hypertension and cardiovascular morbidity (8). Moreover, in patients with essential hypertension who typically lack overt signs of RAS activation, ACE inhibitors and angiotensin receptor blockers (ARBs) effectively reduce blood pressure and ameliorate cardiovascular complications (9-11), suggesting that dysregulation of the RAS contributes to their elevated blood pressure.

Role of the renin-angiotensin system in autoimmune inflammation of the central nervous system

“…In mice, AngII exerts its actions on the cardiovascular and renal systems, mainly via interaction with the AngII type-1a receptor (AT1aR) and type-1b receptor (AT1bR). AngII enhances the release of catecholamines from the adrenal gland and nerve terminals, increases thirst, and promotes salt retention and vasoconstriction, thus significantly contributing to the development of hypertension (2). Moreover, AngII promotes the development of atherosclerosis where the pathogenic role of AngII has been linked to the monocyte chemoattractant protein CCL2 and its receptor CCR2 (3,4).…”

The control of Ca 2+ influx and NFATc3 signaling in arterial smooth muscle during hypertension

“…A rterial tone is elevated during hypertension, increasing the probability of stroke, coronary artery disease, cardiac hypertrophy, and renal failure (1,2). Although the etiology of arterial dysfunction during hypertension is unclear, multiple studies suggest that increased L-type Ca 2ϩ channel (LTCC) activity in arterial smooth muscle is a major contributor to this pathological change (3,4).…”

Roles of cGMP-dependent protein kinase I (cGKI) and PDE5 in the regulation of Ang II-induced cardiac hypertrophy and fibrosis

“…However, selective deletion of the AII receptor 1 (AT-R1) in the kidney ameliorated AIIinduced cardiac hypertrophy, suggesting that the cardiac AT-R1 is dispensable for the induction of this response (6), whereas transgenic mice that overexpress the human AT-R1 specifically in CMs develop hypertrophy, fibrosis, dysfunctions, and early death (7). Furthermore, activation of TRPC channels followed by elevated [Ca 2+ ] i may contribute to the induction of the cardiac hypertrophy gene response (8)(9)(10)(11).…”