Collecting duct-specific knockout of the endothelin A receptor alters renal vasopressin responsiveness, but not sodium excretion or blood pressure

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Abstract
Collecting duct (CD)-specific knockout (KO) of endothelin-1 (ET-1) causes hypertension, impaired ability to excrete a Na load, and enhanced CD sensitivity to the hydrosmotic effects of vasopressin (AVP). CD express the two known ET receptors, ETAand ETB; in the current study, the role of the CD ETAreceptor in mediating ET-1 actions on this nephron segment was evaluated. The ETAreceptor gene was selectively disrupted in CD (CD ETAKO). CD ETAKO mice had no differences in systemic blood pressure, Na or K excretion, and plasma aldosterone or renin activity in response to a normal- or a high-Na diet compared with controls. During normal water intake, urinary osmolality (Uosm), plasma Na concentration, and plasma osmolality were not affected, but plasma AVP concentration was increased in CD ETAKO animals (0.57 ± 0.25 pg/ml in controls and 1.30 ± 0.29 pg/ml in CD ETAKO mice). CD ETAKO mice had a modestly enhanced ability to excrete an acute, but not a chronic, water load. DDAVP infusion increased Uosm similarly; however, CD ETAKO mice had a more rapid subsequent fall in Uosm during sustained DDAVP administration. CD suspensions from CD ETAKO mice had a 30–40% reduction in AVP- and forskolin-stimulated cAMP accumulation. These data indicate that CD ETAKO decreases renal sensitivity to the urinary concentrating effects of AVP and suggest that activation of the ETAreceptor downregulates ET-1 inhibition of AVP actions in the CD. Furthermore, the CD ETAreceptor does not appear to be involved in modulation of systemic blood pressure or renal Na excretion under physiological conditions.