title: Collecting duct-specific knockout of the endothelin A receptor alters renal vasopressin responsiveness, but not sodium excretion or blood pressure.
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, ET(A) and ET(B); in the current study, the role of the CD ET(A) receptor in mediating ET-1 actions on this nephron segment was evaluated. The ET(A) receptor gene was selectively disrupted in CD (CD ET(A) KO). CD ET(A) 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 ET(A) KO animals (0.57 +/- 0.25 pg/ml in controls and 1.30 +/- 0.29 pg/ml in CD ET(A) KO mice). CD ET(A) KO mice had a modestly enhanced ability to excrete an acute, but not a chronic, water load. DDAVP infusion increased Uosm similarly; however, CD ET(A) KO mice had a more rapid subsequent fall in Uosm during sustained DDAVP administration. CD suspensions from CD ET(A) KO mice had a 30-40% reduction in AVP- and forskolin-stimulated cAMP accumulation. These data indicate that CD ET(A) KO decreases renal sensitivity to the urinary concentrating effects of AVP and suggest that activation of the ET(A) receptor downregulates ET-1 inhibition of AVP actions in the CD. Furthermore, the CD ET(A) receptor does not appear to be involved in modulation of systemic blood pressure or renal Na excretion under physiological conditions.
authors.affiliation: Division of Nephrology, Univ. of Utah Health Sciences Center, 1900 East, 30 North, Salt Lake City, UT 84132, USA.
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Ge
authors.forename: Peter K
authors.initials: PK
authors.lastname: Stricklett
authors.forename: Alisa K
authors.initials: AK
authors.lastname: Hughes
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: Donald E
authors.initials: DE
authors.lastname: Kohan
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism / Q000502:physiology; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D004032:Diet; D005838:Genotype; D007668:Kidney / Q000502:physiology*; D007685:Kidney Tubules, Collecting / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D044022:Receptor, Endothelin A / Q000235:genetics* / Q000502:physiology*; D012079:Renal Circulation / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012964:Sodium / Q000652:urine*; D014667:Vasopressins / Q000502:physiology*; D014882:Water-Electrolyte Balance / Q000502:physiology
chemical_list: D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D014667:Vasopressins; D005576:Colforsin; D004247:DNA; D012964:Sodium; D000242:Cyclic AMP; D003894:Deamino Arginine Vasopressin