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1 Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, UT, USA
2 Howard Hughes Medical Institute, University of Texas Southwestern, Dallas, TX, USA
3 Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, UT, USA; Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT, USA
* To whom correspondence should be addressed. E-mail: donald.kohan{at}hsc.utah.edu.
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 hydroosmotic 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 high Na diet as compared to 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 cyclic AMP 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 physiologic conditions.
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