Collecting duct-specific knockout of the endothelin B receptor causes hypertension and sodium retention

Abstract

. Collecting duct-specific knockout of the endothelin B receptor causes hypertension and sodium retention. Am J Physiol Renal Physiol 291: F1274 -F1280, 2006. First published July 25, 2006 doi:10.1152/ajprenal.00190.2006.-Collecting duct (CD)-derived endothelin-1 (ET-1) inhibits renal Na reabsorption and its deficiency increases blood pressure (BP). The role of CD endothelin B (ETB) receptors in mediating these effects is unknown. CD-specific knockout of the ETB receptor was achieved using an aquaporin-2 promoter-Cre recombinase transgene and the loxP-flanked ETB receptor gene (CD ETB KO). Systolic BP in mice with CD-specific knockout of the ETB receptor, ETA receptor (CD ETA KO) and ET-1 (CD ET-1 KO), and their respective controls were compared during normal-and high-salt diet. On a normal-sodium diet, CD ETB KO mice had elevated BP, which increased further during high salt feeding. However, the degree of hypertension in CD ETB KO mice and the further increase in BP during salt feeding were lower than that of CD ET-1 KO mice, whereas CD ETA KO mice were normotensive. CD ETB KO mice had impaired sodium excretion following acute sodium loading. Aldosterone and plasma renin activity were decreased in CD ETB KO mice on normal-and high-sodium diets, while plasma and urinary ET-1 levels did not differ from controls. In conclusion, the CD ETB receptor partially mediates the antihypertensive and natriuretic effects of ET-1. CD ETA and ETB receptors do not fully account for the antihypertensive and natriuretic effects of CD-derived ET-1, suggesting paracrine effects of this peptide. blood pressure; urinary sodium excretion; cell-specific gene targeting NUMEROUS LINES OF EVIDENCE indicate that collecting duct (CD)-derived endothelin-1 (ET-1) is an important regulator of renal Na reabsorption and systemic blood pressure (BP). First, the CD is the major renal site of ET-1 production (8,25,41,48,49), synthesizing more of the peptide than any other cell type (24). Second, the distribution of ET receptors in the kidney closely corresponds to the sites of ET production. Binding and RT-PCR studies using microdissected nephron segments indicate that endothelin receptors are primarily expressed by the inner medullary CD, moderately expressed by outer medullary CD and cortical CD, with much lower expression by other nephron segments (43,45). Third, cultured inner medullary CD cells secrete ET-1 from, and bind ET-1 to, the same (basolateral) side (27). Fourth, in vitro studies indicate that ET-1 inhibits CD Na transport. ET-1 decreases Na reabsorption by the isolated CD, an effect that may be mediated by inhibition of amiloride-sensitive sodium channel activity (14,31,32,46) and/or Na-K-ATPase activity (53). Perhaps the most compelling evidence implicating CD-derived ET-1 in the regulation of renal Na excretion and BP comes from gene targeting studies. Mice with CD-specific knockout of the ET-1 gene (CD ET-1 KO) are hypertensive on a normal-Na diet and this is exacerbated by high Na intake, with systolic BP increasing by almost 40...

Adverse effects of pneumoperitoneum on renal function: involvement of the endothelin and nitric oxide systems

“…Similarly, Mattson et al (32) have demonstrated that chronic intravenous administration of the NO synthase inhibitor N G -nitro-L-arginine methyl ester (L-NAME) selectively decreases renal medullary blood flow, causes sodium and water retention, and leads to hypertension. Similar manifestations were noticed in rats with collecting duct-specific knockout to the ET B receptor (12). Taken together, these findings appeal to the notion that alterations in the endogenous NO system may contribute to the altered renal hemodynamics and kidney function seen in pneumoperitoneum.…”

TASK channel deletion in mice causes primary hyperaldosteronism

“…Urinary aldosterone concentration was determined by solid-phase RIA after extraction with ethylacetate (100%) according to the manufacturer's instructions (Siemens Medical), as described in ref. 46. In separate studies, we determined that acid hydrolysis (3.2 NHCl, 24 h, room temperature, in the dark) was not necessary; hydrolysis reduced measured values by Ͻ5% (97.7 Ϯ 3.8%).…”

Arterial Hypertension Induced by Erythropoietin and Erythropoiesis-Stimulating Agents (ESA)

“…The effect of Epo to increase renal NO production could be the consequence of the increase in ET-1 production, which is a well characterized stimulus for renal NO production. ET-1-induced renal NO production inhibits collecting duct sodium reabsorption in sufficient magnitude to lower BP in mice (60), conferring a potential counter-regulatory mechanism against Epo-induced hypertension and perhaps partially explaining the hypertensive response to l-NAME in Epo-treated rats and rabbits (55,56). Because the renal effect is likely to be less important for BP control in patients with more advanced GFR reduction, such patients may be more predisposed to hypertension.…”