Impaired solute accumulation in inner medulla ofClcnk1−/− mice kidney

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Abstract
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 inClcnk1−/− mice resulted from an impairment in the generation of inner medullary hypertonicity by a dysfunction of the countercurrent systems.