Collecting duct-specific endothelin B receptor knockout increases ENaC activity

Sep 16, 2011American journal of physiology. Cell physiology

Removing endothelin B receptors in kidney collecting ducts increases sodium channel activity

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Abstract

ET-1 significantly decreased ENaC open probability in CD isolated from wild-type and CD ETA KO mice.

ET-1 signaling through ETB receptors is linked to reduced activity of the epithelial Na(+) channel (ENaC) in the collecting duct.
Compromise of ETB receptor function results in elevated ENaC activity across various dietary sodium regimens.
ENaC activity is inversely related to dietary sodium intake in mice with intact ETB receptors but not in those lacking ETB or both ETB and ETA receptors.
Increased ENaC activity in ETB and ETA/B receptor knockout mice may contribute to sodium retention and higher blood pressure.
These findings suggest that ETB receptor activity plays a critical role in regulating sodium excretion and blood pressure through ENaC modulation.

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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.

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Collecting duct-specific endothelin B receptor knockout increases ENaC activity

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