Collecting duct–specific knockout of endothelin-1 causes hypertension and sodium retention

Abstract

In vitro studies suggest that collecting duct-derived (CD-derived) endothelin-1 (ET-1) can regulate renal Na reabsorption; however, the physiologic role of CD-derived ET-1 is unknown.Consequently, the physiologic effect of selective disruption of the ET-1 gene in the CD of mice was determined.Mice heterozygous for aquaporin2 promoter Cre recombinase and homozygous for loxP-flanked exon 2 of the ET-1 gene (called CD-specific KO of ET-1 [CD ET-1 KO] mice) were generated.These animals had no CD ET-1 mRNA and had reduced urinary ET-1 excretion.CD ET-1 KO mice on a normal Na diet were hypertensive, while body weight, Na excretion, urinary aldosterone excretion, and plasma renin activity were unchanged.CD ET-1 KO mice on a high-Na diet had worsened hypertension, reduced urinary Na excretion, and excessive weight gain, but showed no differences between aldosterone excretion and plasma renin activity.Amiloride or furosemide reduced BP in CD ET-1 KO mice on a normal or high-Na diet and prevented excessive Na retention in salt-loaded CD ET-1 KO mice.These studies indicate that CD-derived ET-1 is an important physiologic regulator of renal Na excretion and systemic BP.Nonstandard abbreviations used: aquaporin2 (AQP2); collecting duct (CD); cortical CD (CCD); digitonin (DIG); endothelin (ET); epithelial Na channel (ENaC); ET B receptor (ETRB); inner medullary CD (IMCD); medullary blood flow (MBF); plasma renin activity (PRA); vasopressin (AVP).