Collecting duct-specific knockout of endothelin-1 alters vasopressin regulation of urine osmolality.
In vitro studies suggest that endothelin-1 (ET-1) inhibits vasopressin (AVP)-stimulated water permeability in the collecting duct (CD). To evaluate the role of CD-derived ET-1 in regulating renal water metabolism, the ET-1 gene was selectively disrupted in the CD (CD ET-1 KO). During normal water intake, urinary osmolality (Uosm), plasma Na concentration, urine volume, and renal aquaporin-2 (AQP2) levels were unchanged, but plasma AVP concentration was reduced in CD ET-1 KO animals. CD ET-1 KO mice had impaired ability to excrete an acute, but not a chronic, water load, and this was associated with increased CD ET-1 mRNA in control, but not CD ET-1 KO, mice. In response to continuous infusion of 1-desamino-8-D-arginine vasopressin, CD ET-1 KO mice had greater increases in Uosm, V2 and AQP2 mRNA, and phosphorylation of AQP2. CD suspensions from CD ET-1 KO mice had enhanced AVP- and forskolin-stimulated cAMP accumulation. These data indicate that CD ET-1 KO increases renal sensitivity to the urinary concentrating effects of AVP and suggest that ET-1 functions as a physiological autocrine regulator of AVP action in the CD.
Ge
Yuqiang
Y
Division of Nephrology, University of Utah Health Sciences Center, 30 North 1900 East, Salt Lake City, Utah 84132, USA.
Ahn
Dowahn
D
Stricklett
Peter K
PK
Hughes
Alisa K
AK
Yanagisawa
Masashi
M
Verbalis
Joseph G
JG
Kohan
Donald E
DE
D000818:Animals; D051399:Aquaporin 2; D020346:Aquaporins / Q000235:genetics; D000242:Cyclic AMP / Q000378:metabolism; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D004326:Drinking / Q000502:physiology; D019332:Endothelin-1 / Q000235:genetics* / Q000378:metabolism*; D019426:Integrases / Q000235:genetics; D007685:Kidney Tubules, Collecting / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009994:Osmolar Concentration; D011401:Promoter Regions, Genetic; D017483:Receptors, Vasopressin / Q000235:genetics; D012076:Renal Agents / Q000494:pharmacology; D014556:Urine; D014667:Vasopressins / Q000378:metabolism*; D014867:Water / Q000378:metabolism; D014882:Water-Electrolyte Balance / Q000187:drug effects / Q000502:physiology*
C496024:Aqp2 protein, mouse; D051399:Aquaporin 2; D020346:Aquaporins; D019332:Endothelin-1; D017483:Receptors, Vasopressin; D012076:Renal Agents; D014867:Water; D014667:Vasopressins; D000242:Cyclic AMP; C045073:Cre recombinase; D019426:Integrases; D003894:Deamino Arginine Vasopressin