ENaC Activity is Increased By Collecting Duct‐Specific Endothelin B Receptor Knockout

Abstract

Collecting duct (CD)‐derived endothelin‐1 (ET‐1) acting via endothelin B (ETB) receptors favors Na+ excretion. Compromise of ET‐1 signaling or ETB receptors in the CD cause Na+ retention and increase blood pressure. Activity of ENaC is limiting for Na+ reabsorption in the CD. To test for ETB receptor regulation of ENaC, we combined patch clamp method with CD‐specific knockout of endothelin receptors. We tested how ET‐1 signaling via specific ET receptors influences ENaC activity under differing dietary Na+ regimens. ET‐1 significantly decreased ENaC activity in CD isolated from wt and CD ETA KO mice but not CD ETB KO and CD ETA/B KO mice. ENaC activity was inversely related to dietary Na+ intake. ENaC activity in CD ETB KO and CD ETA/B KO mice tended to be elevated under all dietary Na+ regimens compared to wt and CD ETA KO mice, reaching significance with high (2%) Na+‐feeding. In CD ETB KO and ETA/B KO mice ENaC activity is less responsive to changes in dietary Na+ than wt being inappropriately elevated in the presence of high Na+. These results show that the bulk of ET‐1 inhibition of ENaC activity is mediated by the ETB receptor. In addition, they could explain the Na+ retention and elevated blood pressure observed in CD ET‐1 KO, CD ETB KO and CD ETA/B KO mice consistent with ENaC regulation by ET‐1 via ETB receptors contributing to the antihypertensive and natriuretic effects of the local endothelin system in the mammalian CD.