Collecting duct–specific knockout of endothelin-1 causes hypertension and sodium retention

Abstract

In vitro studies suggest that collecting duct-derived (CD-derived) endothelin-1 (ET-1) can regulate renal Na reabsorption; however, the physiologic role of CD-derived ET-1 is unknown. Consequently, the physiologic effect of selective disruption of the ET-1 gene in the CD of mice was determined. Mice heterozygous for aquaporin2 promoter Cre recombinase and homozygous for loxP-flanked exon 2 of the ET-1 gene (called CD-specific KO of ET-1 [CD ET-1 KO] mice) were generated. These animals had no CD ET-1 mRNA and had reduced urinary ET-1 excretion. CD ET-1 KO mice on a normal Na diet were hypertensive, while body weight, Na excretion, urinary aldosterone excretion, and plasma renin activity were unchanged. CD ET-1 KO mice on a high-Na diet had worsened hypertension, reduced urinary Na excretion, and excessive weight gain, but showed no differences between aldosterone excretion and plasma renin activity. Amiloride or furosemide reduced BP in CD ET-1 KO mice on a normal or high-Na diet and prevented excessive Na retention in salt-loaded CD ET-1 KO mice. These studies indicate that CD-derived ET-1 is an important physiologic regulator of renal Na excretion and systemic BP. IntroductionEndothelin-1 (ET-1) was initially described as a potent endothelial cell-derived vasoconstrictor (1); however, the peptide is now known to be produced by many cell types and to elicit multiple biologic effects (2). The kidney is likely an important target; ET-1 causes renal vasoconstriction, mesangial cell contraction, glomerular cell proliferation, ECM accumulation, and alterations in nephron fluid and electrolyte transport (2). While many renal cell types synthesize and bind ET-1, the collecting duct (CD) is of particular importance: The renal inner medulla contains the highest concentration of ET-1 in the body (3), and the inner medullary CD (IMCD) is the predominant renal site of ET-1 production (4-8) and receptor expression (9-11).In vitro studies suggest that ET-1 inhibits Na and water reabsorption in the cortical CD (CCD) and IMCD and that this occurs through activation of the ET B receptor (ETRB). ET-1 inhibits vasopressin-stimulated (AVP-stimulated) water flux in isolated CCD (9, 12) and reduces AVP-stimulated cyclic AMP accumulation (13-15) and osmotic water permeability (16, 17) in isolated IMCDs. ET-1 also inhibits mineralocorticoid and AVP-stimulated Na and Cl reabsorption in isolated CCDs (12,18,19) and decreases Na/K-ATPase activity in suspensions of IMCDs (20). Despite these data, demonstrating such an ET-1 effect in vivo and clarifying how CD-derived ET-1 physiologically regulates Na and water transport has been problematic. This difficulty stems, in part, from

Endothelin and endothelin receptors in the renal and cardiovascular systems

“…This is in line with the lower BP observed in single KO compared to CD-ET-1 KO mice under high-salt diet (Ge et al, 2006. Hypotensive effect of furosemide in CD-ET-1 KO mice and amiloride in CD-ET-1 KO mice and ET B -KO rats confirm the role of ET-1/ET B on the activity of Na + /K + /Cl − cotransporter and ENaC channel, respectively (Gariepy et al, 2000;Ahn et al, 2004).…”

Endothelin-1 and hypertension: From bench to bedside

“…Because salt-loaded CD ET-1 knockout mice retained sodium, gained more weight, and were markedly hypertensive as compared with control mice, one would expect that the RAAS would be more suppressed in the knockout animals. However, neither plasma renin activity nor urinary aldosterone excretion were altered by CD ET-1 knockout [10]. This inappropriate failure to suppress the renin-aldosterone axis raises the possibility that CDderived ET-1 may, by undetermined mechanisms, reduce activity of this system.…”

“…Administration of an ETRB antagonist directly into the renal medulla of rats decreases urinary sodium and water excretion [9]. To address the physiologic relevance of the CD ET system in regulating blood pressure and sodium excretion, the ET-1 gene was selectively disrupted in CD in mice (CD ET-1 knockout) [10]. CD ET-1 knockout caused hypertension on a normal-salt diet (about 20 mm Hg greater than controls) that was exacerbated by high salt intake (about 35 mm Hg greater than controls).…”

Developmental origins of adult hypertension: new insights into the role of the kidney

“…Recent advances in renal physiology have begun to delineate the roles of intrarenal autocrine, paracrine, and physical factors in normal and abnormal control of Na reabsorption. For instance, endothelin and its B-type receptor [20,21], nitric oxide [22], angiotensin II, prostaglandins [23], and medullary blood flow [24] all participate in the regulation of Na reabsorption, and these systems can be individually manipulated to induce hypertension. Counterregulatory effects on blood pressure may be mediated via locally released NO which suppresses Na transport [22], and decreased NO bioavailability within the kidney has been implicated in the development of hypertension [25].…”