title: Double knockout of pendrin and Na-Cl cotransporter (NCC) causes severe salt wasting, volume depletion, and renal failure.
abstract: The Na-Cl cotransporter (NCC), which is the target of inhibition by thiazides, is located in close proximity to the chloride-absorbing transporter pendrin in the kidney distal nephron. Single deletion of pendrin or NCC does not cause salt wasting or excessive diuresis under basal conditions, raising the possibility that these transporters are predominantly active during salt depletion or in response to excess aldosterone. We hypothesized that pendrin and NCC compensate for loss of function of the other under basal conditions, thereby masking the role that each plays in salt absorption. To test our hypothesis, we generated pendrin/NCC double knockout (KO) mice by crossing pendrin KO mice with NCC KO mice. Pendrin/NCC double KO mice displayed severe salt wasting and sharp increase in urine output under basal conditions. As a result, animals developed profound volume depletion, renal failure, and metabolic alkalosis without hypokalemia, which were all corrected with salt replacement. We propose that the combined inhibition of pendrin and NCC can provide a strong diuretic regimen without causing hypokalemia for patients with fluid overload, including patients with congestive heart failure, nephrotic syndrome, diuretic resistance, or generalized edema.
authors: Research Services, Veterans Affairs Medical Center, Cincinnati, OH 45202, USA. manoocher.soleimani@uc.edu
authors: Manoocher
authors: M
authors: Soleimani
authors: Sharon
authors: S
authors: Barone
authors: Jie
authors: J
authors: Xu
authors: Gary E
authors: GE
authors: Shull
authors: Faraz
authors: F
authors: Siddiqui
authors: Kamyar
authors: K
authors: Zahedi
authors: Hassane
authors: H
authors: Amlal
mesh_terms: D000471:Alkalosis / Q000097:blood / Q000150:complications / Q000503:physiopathology; D000818:Animals; D027321:Anion Transport Proteins / Q000172:deficiency* / Q000378:metabolism; D001835:Body Weight; D004231:Diuresis / Q000502:physiology*; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D007677:Kidney Function Tests; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D011188:Potassium / Q000097:blood; D011955:Receptors, Drug / Q000172:deficiency* / Q000378:metabolism; D051437:Renal Insufficiency / Q000097:blood / Q000150:complications / Q000503:physiopathology*; D012964:Sodium / Q000097:blood; D012965:Sodium Chloride / Q000378:metabolism*; D017673:Sodium Chloride, Dietary; D064486:Solute Carrier Family 12, Member 3; D000076988:Sulfate Transporters; D027981:Symporters / Q000172:deficiency* / Q000378:metabolism; D014667:Vasopressins / Q000008:administration & dosage / Q000494:pharmacology; D014882:Water-Electrolyte Balance / Q000502:physiology
chemical_list: D027321:Anion Transport Proteins; D011955:Receptors, Drug; C578875:Slc12a3 protein, mouse; C494849:Slc26a4 protein, mouse; D017673:Sodium Chloride, Dietary; D064486:Solute Carrier Family 12, Member 3; D000076988:Sulfate Transporters; D027981:Symporters; D014667:Vasopressins; D012965:Sodium Chloride; D012964:Sodium; D011188:Potassium