title: Collecting duct-specific endothelin B receptor knockout increases ENaC activity.
abstract: Collecting duct (CD)-derived endothelin-1 (ET-1) acting via endothelin B (ETB) receptors promotes Na(+) excretion. Compromise of ET-1 signaling or ETB receptors in the CD cause sodium retention and increase blood pressure. Activity of the epithelial Na(+) channel (ENaC) is limiting for Na(+) reabsorption in the CD. To test for ETB receptor regulation of ENaC, we combined patch-clamp electrophysiology with CD-specific knockout (KO) of endothelin receptors. We also tested how ET-1 signaling via specific endothelin receptors influences ENaC activity under differing dietary Na(+) regimens. ET-1 significantly decreased ENaC open probability in CD isolated from wild-type (WT) and CD ETA KO mice but not CD ETB KO and CD ETA/B KO mice. ENaC activity in WT and CD ETA but not CD ETB and CD ETA/B KO mice was inversely related to dietary Na(+) intake. ENaC activity in CD ETB and CD ETA/B KO mice tended to be elevated under all dietary Na(+) regimens compared with WT and CD ETA KO mice, reaching significance with high (2%) Na(+) feeding. 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.
authors.affiliation: Department of Physiology, University of Texas Health Sciences Center, San Antonio, Texas 78229, USA.
authors.forename: Vladislav
authors.initials: V
authors.lastname: Bugaj
authors.forename: Elena
authors.initials: E
authors.lastname: Mironova
authors.forename: Donald E
authors.initials: DE
authors.lastname: Kohan
authors.forename: James D
authors.initials: JD
authors.lastname: Stockand
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D019332:Endothelin-1 / Q000378:metabolism / Q000502:physiology; D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D005260:Female; D006973:Hypertension / Q000235:genetics / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009318:Natriuresis / Q000235:genetics; D044023:Receptor, Endothelin B / Q000172:deficiency* / Q000235:genetics*; D012964:Sodium / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D019332:Endothelin-1; D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels; D044023:Receptor, Endothelin B; D000584:Amiloride; D012964:Sodium