title: Endothelin and collecting duct sodium and water transport.
abstract: The renal collecting duct (CD) produces and binds more endothelin (ET)-1 than any other region of the kidney. ET-1 has the potential to act as an autocrine regulator of CD function since ET-1 is secreted abluminally and ET receptors are located primarily on the basolateral side of the CD cell. A large number of in vitro studies have supported this notion of an autocrine function for ET-1, demonstrating that the peptide, largely through activation of the ET(B) receptor, inhibits both sodium (Na) and water reabsorption in the CD. The physiologic relevance of these findings has been confirmed in vivo wherein mice with CD-specific knockout of ET-1 are hypertensive on a normal Na diet and develop worsened hypertension associated with Na retention when placed on a high-Na diet. Similarly, CDET-1-deficient mice demonstrate enhanced responsiveness to vasopressin and an impaired ability to excrete an acute water load. CD-specific knockout of both ET(A) and ET(B) receptors together causes a similar hypertensive and Na-retaining phenotype. The mechanisms by which ET-1 exerts its effects on CD Na and water reabsorption are being increasingly understood. ET-1 inhibits epithelial Na channel (ENaC) activity through src- and mitogen-activated protein kinase-dependent pathways; channel number is also reduced by a β1Pix-dependent mechanism. In addition, nitric oxide is an important modulator of ET-1 actions on the ENaC, although the mechanism by which this occurs remains to be determined. ET-1 reduces CD water reabsorption by inhibition of vasopressin-stimulated adenylyl cyclase activity through G(i) and protein kinase C-dependent pathways, leading to a reduction in cellular cAMP levels. Taken together, these findings indicate that the CD ET system is an important physiologic regulator of systemic blood pressure and volume homeostasis.
authors: Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.
authors: Donald E
authors: DE
authors: Kohan
mesh_terms: D000818:Animals; D001834:Body Water / Q000378:metabolism*; D016232:Endothelins / Q000502:physiology*; D006801:Humans; D017136:Ion Transport; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D017466:Receptors, Endothelin / Q000502:physiology; D012964:Sodium / Q000378:metabolism*
chemical_list: D016232:Endothelins; D017466:Receptors, Endothelin; D012964:Sodium