Tacrolimus ameliorates the phenotypes of type 4 Bartter syndrome model mice through activation of sodium?potassium?2 chloride cotransporter and sodium?chloride cotransporter
Tacrolimus ameliorates the phenotypes of type 4 Bartter syndrome model mice through activation of sodium?potassium?2 chloride cotransporter and sodium?chloride cotransporter
复制标题
他克莫司通过激活钠·钾·2氯化物协同转运蛋白和钠·氯化物协同转运蛋白改善4型巴特综合征模型小鼠的表型
DOI：
10.1016/j.bbrc.2019.07.086
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发表时间：
2019
影响因子：
3.1
通讯作者：
Uchida Shinichi
中科院分区：
文献类型：
--
作者：
Matsuura Yoshiaki;Nomura Naohiro;Shoda Wakana;Mori Takayasu;Isobe Kiyoshi;Susa Koichiro;Ando Fumiaki;Sohara Eisei;Rai Tatemitsu;Uchida Shinichi
4型巴特尔综合征（Type 4 Bartter syndrome， BS）是由bsnd编码的巴特尔素基因突变引起的。巴丁蛋白是Cl - k氯离子（Cl−）通道的β-亚基，广泛表达于远端肾单位。4型BS的特点是盐的重吸收严重受损，可引起多尿、低钾血症和代谢性碱中毒。据报道，钙调磷酸酶抑制剂通过增强钠(Na+) -钾(K+) -2Cl -共转运体（NKCC2）和钠+ -Cl -共转运体（NCC）的磷酸化诱导肾盐潴留和高钾血症。此外，我们以前报道过他克莫司，一种钙调神经磷酸酶抑制剂，增加磷酸化NCC的水平。在这项研究中，我们将他克莫司给予巴丁畸形（Bsndneo/neo）小鼠，这是一种表现出多尿、低钾血症和代谢性碱中毒的4型BS小鼠模型。他克莫司可提高血清钾离子水平，抑制尿钾离子排泄。此外，在他克莫司治疗后，Bsndneo/neomice增加了磷酸化的NCC和NKCC2的水平。我们得出结论，他克莫司可以部分改善bsndneo /neomice的临床表型，钙调磷酸酶抑制剂可能对治疗4型BS有效。
Type 4 Bartter syndrome (BS) is caused by genetic mutations in barttin, which is coded for byBSND. 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 (Bsndneo/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,Bsndneo/neomice increased levels of phosphorylated NCC and NKCC2. We conclude that tacrolimus partially improves clinical phenotypes ofBsndneo/neomice, and that calcineurin inhibitors might be effective for treating type 4 BS.