Collecting duct-specific endothelin B receptor knockout increases ENaC activity.

Area of Science:

• Physiology
• Nephrology
• Cardiovascular Biology

Background:

• Collecting duct (CD)-derived endothelin-1 (ET-1) signaling via endothelin B (ETB) receptors promotes sodium (Na+) excretion.
• Disruptions in ET-1 or ETB receptor function in the CD lead to sodium retention and hypertension.
• Epithelial sodium channel (ENaC) activity is a key determinant of Na+ reabsorption in the CD.

Purpose of the Study:

• To investigate the role of ETB receptors in regulating ENaC activity in the collecting duct.
• To determine how ET-1 signaling through specific endothelin receptors influences ENaC activity under varying dietary sodium conditions.

Main Methods:

• Patch-clamp electrophysiology was employed to measure ENaC activity.
• Collecting duct-specific knockout (KO) mouse models for endothelin receptors (ETA, ETB, and ETA/B) were utilized.
• Experiments were conducted under different dietary sodium intake regimens.

Main Results:

• ET-1 significantly reduced ENaC open probability in wild-type (WT) and CD ETA KO mice, but not in CD ETB KO and CD ETA/B KO mice.
• ENaC activity in WT and CD ETA KO mice showed an inverse relationship with dietary Na+ intake, unlike in CD ETB and CD ETA/B KO mice.
• ENaC activity was elevated in CD ETB and CD ETA/B KO mice across all diets, particularly with high sodium intake.

Conclusions:

• The majority of ET-1's inhibitory effect on ENaC activity is mediated by the ETB receptor.
• ET-1 regulation of ENaC via ETB receptors in the CD contributes to the antihypertensive and natriuretic effects of the local endothelin system.
• These findings help explain sodium retention and elevated blood pressure observed in mice with compromised CD ET-1 or ETB receptor signaling.