Salt‐Losing Nephropathy in Mice with a Null Mutation of Clcnkb

The basolateral chloride channel CLCKb facilitates Cl reabsorption in the distal nephron. Mutations in clcnkb were associated with Bartter's syndrome type 3 in humans. To address the function of clcnkb for renal salt reabsorption, we generated a mouse line with a null mutation of clcnkb by the use of the Zn finger technology. Clcnkb‐deficient mice were viable and were born in Mendelian ratio. At the age of 4 weeks, clcnkb−/− mice showed a slight growth retardation, with a body weight of 14.0±0.5 g compared with 19.7±0.5 g in WT (p<0.0001). Ambient urine osmolarity was markedly reduced in Clcnkb‐deficient mice (590±39 vs. 2216±132 mosmol/L in WT; p<0.0001). During water restriction (12 hrs), urinary osmolarity increased to 1633±153 mosmol/L and 3769±129 mosmol/L in clcnkb−/− and WT mice (n=12; p<0.0001), which was accompanied by a loss of body weight of 12±0.4% and 8±0.2%, respectively (p<0.0001). Fractional urinary K + excretion averaged 0.21±0.02 mmol/mosmol (clcnkb−/−) and 0.11±0.01 mmol/mosmol (WT; p=0.0008), suggesting increased K secretion in the collecting duct of clcnkb−/− mice. The salt‐losing phenotype of clcnkb−/− mice was associated with a reduced plasma volume (2.5±0.6% of body weight vs. 3.9±0.2% in WT; p=0.0230), a reduced GFR (1040±97 vs. 1395±129 μl/min/100g bw in WT; n=9; p= 0.0411), and massively increased plasma renin concentrations (35720±8941 vs. 56±8 ng Ang I/ml/min in WT, respectively; n=11; p<0.0001). Our data suggest that clcnkb is crucial for renal salt reabsorption and concentrating ability. Clcnkb‐deficient mice appear as a suitable model of Bartter's syndrome type 3.