Bartter’s syndrome type 1 is caused by loss-of–function mutations of the Na/K/Cl Cotransporter, NKCC2. NKCC2 is expressed in the kidney along the thick ascending limb of Henle (TAL) in three different isoforms, namely NKCC2F, NKCC2A and NKCC2B which are derived from differential splicing of exon 4 of the NKCC2 gene. In most Bartter’s patients functional integrity of all isoforms of NKCC2 is compromised leading to pronounced salt loosing nephropathy. However, single cases of atypical Bartter’s type 1 syndrome with an unusually mild phenotype were reported with one being confirmed to be related to specific inactivation of the B isoform of NKCC2.

To investigate the phenotype of specific inactivation of one single splice isoform of NKCC2 in a mouse model, NKCC2B-deficient mice were generated by gene targeting. NKCC2B-deficient mice showed no gross abnormalities. Relative expression levels and distribution patterns of the remaining NKCC2A and NKCC2F were not altered in NKCC2B-deficient mice. NKCC2B-deficient mice did not display a salt loosing phenotype with basal plasma renin and aldosterone levels being not different from wild type mice. Ambient urine osmolarities, however, were slightly, but significantly reduced. Distal Cl- concentrations were significantly elevated, and loop of Henle Cl- absorption was reduced in microperfused superficial loops of Henle of NKCC2B-deficient mice. Plasma renin concentration in NKCC2B-deficient mice was reduced under conditions of both chronic and acute salt loading compared to wild types. Due to the co-expression of NKCC2A in the macula densa of the TAL, maximum tubuloglomerular feedback (TGF) responses were normal, but TGF function curves were right-shifted indicating reduced sensitivity in the subnormal flow range.

The mild phenotype of mice deficient in the B isoform of NKCC2 indicates a limited role for NKCC2B for overall salt retrieval corresponding to the mild phenotype of Bartter’s patients with mutations in exon 4B of NKCC2. Nevertheless, the high affinity NKCC2B contributes to salt absorption and macula densa function in the low NaCl concentration range. Macula densa control of renin secretion and preglomerular resistance appeared largely preserved due to co-expression of NKCC2A in the macula densa segment of the TAL. Increased distal Cl- concentration in NKCC2B-deficient mice, in concert with expression of NKCC2A in the macula densa segment of the TAL, may contribute to the Bartter-atypical suppression of renin secretion observed under conditions of salt loading.