Endothelin-1 inhibits sodium reabsorption by ET_Aand ET_Breceptors in the mouse cortical collecting duct

Abstract

The collecting duct (CD) is a major renal site for the hormonal regulation of Na homeostasis and is critical for systemic arterial blood pressure control. Our previous studies demonstrated that the endothelin-1 gene (edn1) is an early response gene to the action of aldosterone. Because aldosterone and endothelin-1 (ET-1) have opposing actions on Na reabsorption (JNa) in the kidney, we postulated that stimulation of ET-1 by aldosterone acts as a negative feedback mechanism, acting locally within the CD. Aldosterone is known to increase JNa in the CD, in part, by stimulating the epithelial Na channel (ENaC). In contrast, ET-1 increases Na and water excretion through its binding to receptors in the CD. To date, direct measurement of the quantitative effect of ET-1 on transepithelial JNa in the isolated in vitro microperfused mouse CD has not been determined. We observed that the CD exhibits substantial JNa in male and female mice that is regulated, in part, by a benzamil-sensitive pathway, presumably ENaC. ENaC-mediated JNa is greater in the cortical CD (CCD) than in the outer medullary CD (OMCD); however, benzamil-insensitive JNa is present in the CCD and not in the OMCD. In the presence of ET-1, ENaC-mediated JNa is significantly inhibited. Blockade of either ETA or ETB receptor restored JNa to control rates; however, only ETA receptor blockade restored a benzamil-sensitive component of JNa. We conclude 1) Na reabsorption is mediated by ENaC in the CCD and OMCD and also by an ENaC-independent mechanism in the CCD; and 2) ET-1 inhibits JNa in the CCD through both ETA and ETB receptor-mediated pathways.

Chloride secretion by renal collecting ducts

“…Interestingly, the IMCD is a major site for the production of endothelin-1 (ET-1) [44], which is capable of binding four G αq coupled GPCR isoforms ETA, ETB1, ETB2 and ETC. In the collecting duct, ET-1 binding to ETA or ETB decreases ENaC activity [45, 46]; however, it role in Cl − secretion has not been examined. Recently, glycogen synthase kinase 3β (GSK 3β), a kinase in the Wnt signaling pathway, was shown to stimulate cAMP production by activating adenylyl cyclase in collecting duct cells.…”

The Role of Transforming Growth Factor β1 in the Regulation of Blood Pressure

“…demonstrated that endothelin-1 decreases the activity of ENaC in isolated rat collecting ducts, through ETB, but not ETA receptors [162]. Endothelin-1 decreases sodium reabsorption in isolated mouse collecting ducts, through both ETA and ETB receptors [163]. The inhibition of ENaC by endothelin-1 is abolished by a selective Src kinase inhibitor, PP2 [164].…”

Myocardial, Smooth Muscle, Nephron, and Collecting Duct Gene Targeting Reveals the Organ Sites of Endothelin A Receptor Antagonist Fluid Retention

“…Furthermore, ETA blockade in intact rats reduces the natriuretic and diuretic response to renal medullary infusion of hyperosmotic saline (Boesen and Pollock, 2010). Finally, ET-1 inhibition of amiloride-sensitive transepithelial sodium flux in vitro microperfused mouse collecting duct is prevented by ETA antagonism (Lynch et al, 2013). Thus, collecting-duct ETA may well be capable of inhibiting sodium and water transport.…”