Tacrolimus ameliorates the phenotypes of type 4 Bartter syndrome model mice through activation of sodium-potassium-2 chloride cotransporter and sodium-chloride cotransporter.

Type 4 Bartter syndrome (BS) is caused by genetic mutations in barttin, which is coded for by BSND. Barttin serves as the β-subunit of the ClC-K chloride (Cl^-) channel, which is widely expressed in distal nephrons. Type 4 BS is characterized by severely impaired reabsorption of salt, which may cause polyuria, hypokalemia, and metabolic alkalosis. Calcineurin inhibitors reportedly induce renal salt retention and hyperkalemia by enhancing the phosphorylation of the sodium (Na⁺)-potassium (K⁺)-2Cl^- cotransporter (NKCC2) and Na⁺-Cl^- cotransporter (NCC). In addition, we have previously reported that tacrolimus, a calcineurin inhibitor, increases the levels of phosphorylated NCC. In this study, we administered tacrolimus to barttin hypomorphic (Bsnd^neo/neo) mice, a murine model of type 4 BS that exhibits polyuria, hypokalemia, and metabolic alkalosis. Administration of tacrolimus increased the serum K⁺ level and suppressed urinary K⁺ excretion. Furthermore, after treatment with tacrolimus, Bsnd^neo/neo mice increased levels of phosphorylated NCC and NKCC2. We conclude that tacrolimus partially improves clinical phenotypes of Bsnd^neo/neo mice, and that calcineurin inhibitors might be effective for treating type 4 BS.

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