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

Abstract Type4 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. Calcineurininhibitors reportedly induce renal salt retention and hyperkalemiaby 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 calcineurininhibitor, increases the levels of phosphorylated NCC. In this study, we administered tacrolimusto barttin hypomorphic (Bsndneo/neo) mice, a murine model of type 4 BS that exhibits polyuria, hypokalemia, and metabolic alkalosis. Administration of tacrolimusincreased the serum K+ level and suppressed urinary K+ excretion. Furthermore, after treatment with tacrolimus, Bsndneo/neo mice increased levels of phosphorylated NCC and NKCC2. We conclude that tacrolimuspartially improves clinical phenotypes of Bsndneo/neo mice, and that calcineurininhibitors might be effective for treating type 4 BS.