Impaired solute accumulation in inner medulla of Clcnk1-/- mice kidney.
The CLC-K1 chloride channel is a kidney-specific CLC chloride channel expressed in the thin ascending limb of Henle's loop (tAL). Recently, we determined that Clcnk1-/- mice show nephrogenic diabetes insipidus (NDI). To investigate the pathogenesis of impaired urinary concentrating ability, we analyzed renal functions of Clcnk1-/- mice in more detail. The osmolar clearance-to-creatinine clearance ratio was not significantly different between Clcnk1+/- and Clcnk1+/+ mice. Fractional excretion of sodium, chloride, and urea was also not significantly affected in Clcnk1-/- mice. These results indicate that the polyuria observed in Clcnk1-/- mice was water diuresis and not osmotic diuresis. The papillary osmolarity in Clcnk1-/- mice was significantly lower than that in Clcnk1+/+ mice under a hydrated condition, and it did not increase even after water deprivation. Sodium and chloride contents in the inner medulla in Clcnk1-/- mice were at about one-half the levels observed in Clcnk1+/+ mice. Furthermore, the accumulation of urea was also impaired in Clcnk1-/- mice, suggesting that the overall countercurrent system was impaired by a defect of its single component, chloride transport in the tAL. The aldose reductase mRNA abundance in Clcnk1-/- mice was decreased, further evincing that inner medullary tonicity is decreased in Clcnk1-/- mice. We concluded that NDI in Clcnk1-/- mice resulted from an impairment in the generation of inner medullary hypertonicity by a dysfunction of the countercurrent systems.
Akizuki
N
N
Second Department of Internal Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
Uchida
S
S
Sasaki
S
S
Marumo
F
F
D000449:Aldehyde Reductase / Q000235:genetics; D000450:Aldosterone / Q000097:blood; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D018118:Chloride Channels / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003404:Creatinine / Q000378:metabolism; D003433:Crosses, Genetic; D003681:Dehydration / Q000503:physiopathology; D004231:Diuresis; D050485:GABA Plasma Membrane Transport Proteins; D006579:Heterozygote; D006720:Homozygote; D007679:Kidney Medulla / Q000502:physiology* / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D027361:Organic Anion Transporters; D011141:Polyuria; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic; D014868:Water Deprivation
D002352:Carrier Proteins; D018118:Chloride Channels; C489933:Clcnka protein, mouse; D050485:GABA Plasma Membrane Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D012333:RNA, Messenger; D000450:Aldosterone; D003404:Creatinine; D000449:Aldehyde Reductase