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

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 in Clcnk1-/- mice resulted from an impairment in the generation of inner medullary hypertonicity by a dysfunction of the countercurrent systems.

A mathematical model of the urine concentrating mechanism in the rat renal medulla. II. Functional implications of three-dimensional architecture

“…As a result, only 33.0% of the IMCD fluid flow was reabsorbed, and a urine of a relatively low osmolality of 768 mosmol/kgH 2 O was predicted. These results are in general agreement with experimental findings in transgenic mice (1,7,8). It is noteworthy that in both case, the OM concentrating capability was minimally affected.…”

“…In particular, mice lacking Clc-k1, the chloride transporter found in long-loop prebends and in the thin ascending limbs, have greatly reduced concentrating capability, as do mice lacking UT-A1 and UT-A3, the urea transporters found in the IMCD (1,7,8).…”

Molecular switch for CLC-K Cl − channel block/activation: Optimal pharmacophoric requirements towards high-affinity ligands

“…selective inhibitors of ClC-Ka might primarily interfere with water reabsorption, as suggested by the phenotype resulting from targeted inactivation of the homologous gene in mice (4).…”

Chloride channel diseases resulting from impaired transepithelial transport or vesicular function

“…The targeted disruption of the mouse homolog ClC-K1 leads to a diabetes insipidus-like phenotype (39). This mouse model demonstrates that the large Cl -conductance in the thin limb, which is part of the countercurrent system, is essential for solute accumulation in the inner renal medulla (65).…”

“…α-Intercalated cells (α-IC) secrete protons using a proton ATPase, while basolateral transport of acid equivalents is via the anion exchanger AE1. It is proposed that both KCC4 cotransporters (65) and ClC-K/barttin channels recycle Cl -. It is unknown whether ClC-K/barttin is involved in Cl -reabsorption in β-intercalated cells as shown below.…”