title: A novel target for diuretic therapy.
abstract: The reabsorption of salt in the distal nephron is predominantly mediated via the thiazide-sensitive sodium chroride cotransporter, NCC (SLC12A3), and the chloride-bicarbonate exchanger pendrin (SLC26A4, PDS), with pendrin working in tandem with the epithelial sodium channel and NCC working by itself. Single deletion of NCC or pendrin in genetically engineered mouse models does not cause salt wasting or excessive diuresis under basal conditions. Both pendrin knockout and NCC knockout mice, however, show signs of volume depletion or develop hypotension during salt restriction. These findings have led investigators to conclude that pendrin and NCC are predominantly active during salt depletion and their contribution to salt reabsorption at baseline conditions is small. We hypothesized that pendrin may compensate for loss of NCC under basal conditions, thereby masking the role that each transporter plays in salt reabsorption. To test this hypothesis, double knockout of pendrin and sodium chloride cotransporter was generated by crossing animals with single deletion for NCC and pendrin. The double-knockout mice show significant salt and fluid wasting, along with severe volume depletion, metabolic alkalosis and prerenal failure under baseline conditions. Volume depletion, metabolic alkalosis and prerenal failure were significantly corrected with salt repletion. We conclude that pendrin plays an essential role in the distal tubule salt reabsorption in the setting of sodium-chloride cotransporter inactivation. We propose that pendrin could be a novel target for a new diuretic that in conjunction with thiazide can be an effective regimen for patients with fluid overload.
authors.affiliation: Center on Genetics of Transport and Epithelial Biology and Department of Medicine, University of Cincinnati, Cincinnati, OH 45267-0585, USA. soleimm@ucmail.uc.edu
authors.forename: Manoocher
authors.initials: M
authors.lastname: Soleimani
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D004232:Diuretics / Q000494:pharmacology*; D017353:Gene Deletion; D007685:Kidney Tubules, Collecting / Q000187:drug effects; D007687:Kidney Tubules, Proximal / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D011955:Receptors, Drug / Q000235:genetics; D051437:Renal Insufficiency / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D012965:Sodium Chloride / Q000378:metabolism; D049992:Sodium Chloride Symporters / Q000187:drug effects*; D064486:Solute Carrier Family 12, Member 3; D000076988:Sulfate Transporters; D027981:Symporters / Q000235:genetics; D014882:Water-Electrolyte Balance; D014883:Water-Electrolyte Imbalance / Q000188:drug therapy / Q000235:genetics
chemical_list: D027321:Anion Transport Proteins; D004232:Diuretics; D011955:Receptors, Drug; C578875:Slc12a3 protein, mouse; C494849:Slc26a4 protein, mouse; D049992:Sodium Chloride Symporters; D064486:Solute Carrier Family 12, Member 3; D000076988:Sulfate Transporters; D027981:Symporters; D012965:Sodium Chloride