title: The role of endothelin in proximal tubule proton secretion and the adaptation to a chronic metabolic acidosis.
abstract: The endothelins (ET) are powerful effector agents that control multiple aspects of kidney function. This review will focus on endothelin's effect on proximal tubule H+ secretion. The proximal tubule is responsible for reabsorbing approximately 80% of filtered NaHCO3 by a mechanism mediated by H+ secretion. The major fraction (60-70%) of proximal tubule H+ secretion across the apical membrane is mediated by an amiloride inhibitable Na+/H+ antiporter, while the remaining is mediated by a vaculoar H(+)-ATPase. Molecular, immunocytochemical, and inhibitor sensitivity studies all demonstrate that virtually all proximal tubule apical Na+/H+ activity is mediated by NHE3. Hence, regulation of proximal tubule H+ secretion involves, in most cases, regulation of apical membrane NHE3. We have recently shown that stimulation of NHE3 activity in metabolic acidosis is mediated by endothelin-1 (ET-1) working through the endothelin B (ETB) receptor. ET-1/ETB stimulated antiporter activity is due to an increase in apical membrane NHE3 abundance, achieved by an increase in exocytic insertion of NHE3 into the apical membrane. We have also shown that acid-stimulated NHE3 activity depends on activation of Pyk2, c-Src, MAP kinase, and the immediate early genes c-Fos and c-Jun. This article summarizes these findings and proposes an acid-activated signaling pathway that is responsible for the increase in NHE3 activity in metabolic acidosis.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75390-9003, USA.
authors.forename: Kamel
authors.initials: K
authors.lastname: Laghmani
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Preisig
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Alpern
mesh_terms: D000138:Acidosis / Q000503:physiopathology*; D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D002908:Chronic Disease; D016232:Endothelins / Q000502:physiology*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D011522:Protons
chemical_list: D016232:Endothelins; D011522:Protons