Physiological role of CLC-K1 chloride channel in the kidney.
Although CLC chloride channels share a common structure, the sites of expression in the body and their intracellular localization are different among CLCs. CLC-K1 and -K2 are kidney-specific CLC chloride channels. We have clarified their localization in the plasma membranes of tubular cells by immunohistochemistry and proposed their roles in transepithelial chloride transport. Since there exit no good inhibitors for these channels, a gene knockout approach was the only way to establish their roles in kidney. While we were generating CLC-K knockout mice, Simon et al. reported that the mutations of CLC-K2 in human resulted in Bartter's syndrome. This had been anticipated since CLC-K2 is known to be present in the basolateral plasma membranes of the distal nephron where sodium-dependent chloride transporters are present in the apical membranes. Thus, CLC-K2 constitutes an important route for chloride reabsorption as an exit for chloride ions in the basolateral membrane. Another important finding in Simon's report was that no CLC-K (a human homologue of rat CLC-K1) mutation was found in patients with Bartter's syndrome. This suggested that CLC-K1 has a different role in kidney. We believed this to be true, based on the finding that the intrarenal localization of CLC-K1 and CLC-K2 are completely different. In the CLC-K1 knockout mice, we could clearly verify that (i) the high chloride permeability in the tAL was mediated by CLC-K1 and (ii) this chloride transport is necessary for urinary concentration. Further studies are necessary to elucidate the detailed mechanisms of the urinary-concentrating defect in Clcnk1 -/- mice. Exact clearance studies and measurements of osmolality and solute contents in the inner medulla will provide the answer to this question.
Uchida
S
S
Second Department of Internal Medicine, Tokyo Medical and Dental University, School of Medicine, Japan. suchida.hid2@med.tmd.ac.jp
D000818:Animals; D018118:Chloride Channels / Q000235:genetics / Q000502:physiology*; D007668:Kidney / Q000502:physiology*; D007671:Kidney Concentrating Ability / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout / Q000097:blood / Q000235:genetics / Q000652:urine
C489932:CLCNKA protein, human; D018118:Chloride Channels; C489933:Clcnka protein, mouse