title: Pendrin as a novel target for diuretic therapy.
abstract: The Cl(-)/HCO(3)(-) exchanger pendrin (SLC26A4, PDS) and the thiazide-sensitive NaCl cotransporter NCC (SLC12A3) are expressed on the apical membranes of distal nephron segments and mediate salt absorption, with pendrin working in tandem with the epithelial Na channel (ENaC) and NCC working by itself. Pendrin is expressed on the apical membrane of intercalated cells in late distal convoluted tubule (DCT), connecting tubule (CNT) and the cortical collecting duct (CCD) whereas the thiazide-sensitive NaCl cotransporter NCC is primarily detected on the apical membrane of DCT cells. Recent studies indicate that pendrin expression is increased in kidneys of NCC knockout mice, raising the possibility that pendrin and NCC can compensate for loss of the other by increasing their expression and activity. Current investigations in our laboratories demonstrate that pendrin plays an important role in compensatory salt absorption in response to the loop diuretics and the thiazide derivatives. These studies further demonstrate that whereas single deletion of pendrin or NCC does not cause salt wasting in mutant mice under baseline conditions, double knockout of pendrin and NCC causes profound polyuria and polydipsia, along with salt wasting under basal conditions. As a result, animals develop significant dehydration. We propose that pharmacologic inhibition of pendrin and NCC can provide a novel and strong diuretic regimen for patients with fluid overload, including those with congestive heart failure, nephrotic syndrome or renal failure.
authors: Center on Genetics of Transport and Epithelial Biology and the Department of Medicine, University of Cincinnati, and Research Services, Veterans Administration Hospital, Cincinnati, OH 45267-0585, USA. Amlalh@uc.edu
authors: Hassane
authors: H
authors: Amlal
authors: Manoocher
authors: M
authors: Soleimani
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D004231:Diuresis / Q000502:physiology; D004232:Diuretics / Q000494:pharmacology; D007686:Kidney Tubules, Distal / Q000187:drug effects / Q000378:metabolism; D011955:Receptors, Drug / Q000378:metabolism / Q000502:physiology; D064486:Solute Carrier Family 12, Member 3; D000076988:Sulfate Transporters; D027981:Symporters / Q000378:metabolism / Q000502:physiology; D049971:Thiazides / Q000494:pharmacology
chemical_list: D027321:Anion Transport Proteins; D004232:Diuretics; D011955:Receptors, Drug; C578875:Slc12a3 protein, mouse; C494849:Slc26a4 protein, mouse; D064486:Solute Carrier Family 12, Member 3; D000076988:Sulfate Transporters; D027981:Symporters; D049971:Thiazides