Calcineurin inhibitors block sodium-chloride cotransporter dephosphorylation in response to high potassium intake

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• 作者：Wakana Shoda¹ ; Naohiro Nomura¹ ; ^{nnomura.kid@tmd.ac.jp} ; Fumiaki Ando¹ ; Yutaro Mori¹ ; Takayasu Mori¹ ; Eisei Sohara¹ ; Tatemitsu Rai¹ ; Shinichi Uchida¹
• 关键词：calcineurin ; phosphatase ; potassium ; sodium-chloride cotransporter
• 刊名：Kidney International
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：91
• 期：2
• 页码：402-411
• 全文大小：1109 K
• 卷排序：91

文摘

Dietary potassium intake is inversely related to blood pressure and mortality. Moreover, the sodium-chloride cotransporter (NCC) plays an important role in blood pressure regulation and urinary potassium excretion in response to potassium intake. Previously, it was shown that NCC is activated by the WNK4-SPAK cascade and dephosphorylated by protein phosphatase. However, the mechanism of NCC regulation with acute potassium intake is still unclear. To identify the molecular mechanism of NCC regulation in response to potassium intake, we used adult C57BL/6 mice fed a 1.7% potassium solution by oral gavage. We confirmed that acute potassium load rapidly dephosphorylated NCC, which was not dependent on the accompanying anions. Mice were treated with tacrolimus (calcineurin inhibitor) and W7 (calmodulin inhibitor) before the oral potassium loads. Dephosphorylation of NCC induced by potassium was significantly inhibited by both tacrolimus and W7 treatment. There was no significant difference in WNK4, OSR1, and SPAK expression after high potassium intake, even after tacrolimus and W7 treatment. Another phosphatase, protein phosphatase 1, and its endogenous inhibitor I-1 did not show a significant change after potassium intake. Hyperkaliuria, induced by high potassium intake, was significantly suppressed by tacrolimus treatment. Thus, calcineurin is activated by an acute potassium load, which rapidly dephosphorylates NCC, leading to increased urinary potassium excretion.