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

Yuqiang Ge, Peter K. Stricklett, Alisa K. Hughes, Masashi Yanagisawa, Donald E. Kohan

Research output: Contribution to journalArticle

80 Scopus citations

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, ETA and ETB; in the current study, the role of the CD ETA receptor in mediating ET-1 actions on this nephron segment was evaluated. The ETA receptor gene was selectively disrupted in CD (CD ETA KO). CD ETA KO 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 ETA KO animals (0.57 ± 0.25 pg/ml in controls and 1.30 ± 0.29 pg/ml in CD ETA KO mice). CD ETA KO mice had a modestly enhanced ability to excrete an acute, but not a chronic, water load. DDAVP infusion increased Uosm similarly; however, CD ETA KO mice had a more rapid subsequent fall in Uosm during sustained DDAVP administration. CD suspensions from CD ETA KO mice had a 30-40% reduction in AVP- and forskolin-stimulated cAMP accumulation. These data indicate that CD ETA KO decreases renal sensitivity to the urinary concentrating effects of AVP and suggest that activation of the ETA receptor downregulates ET-1 inhibition of AVP actions in the CD. Furthermore, the CD ETA receptor does not appear to be involved in modulation of systemic blood pressure or renal Na excretion under physiological conditions.

Original languageEnglish (US)
Pages (from-to)F692-F698
JournalAmerican Journal of Physiology - Renal Physiology
Volume289
Issue number4 58-4
DOIs
StatePublished - Oct 2005

Keywords

  • Adenosine 3′,5′-cyclic monophosphate
  • Inner medullary collecting duct
  • Tubule

ASJC Scopus subject areas

  • Physiology
  • Urology

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