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首页> 外文期刊>Biology Open >A minor role of WNK3 in regulating phosphorylation of renal NKCC2 and NCC co-transporters in vivo
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A minor role of WNK3 in regulating phosphorylation of renal NKCC2 and NCC co-transporters in vivo

机译：WNK3在体内调节肾脏NKCC2和NCC共同转运蛋白的次要作用

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Mutations in WNK1 and WNK4 kinase genes have been shown to cause a human hereditary hypertensive disease, pseudohypoaldosteronism type II (PHAII). We previously discovered that WNK kinases phosphorylate and activate OSR1/SPAK kinases that regulate renal SLC12A family transporters such as NKCC2 and NCC, and clarified that the constitutive activation of this cascade causes PHAII. WNK3, another member of the WNK kinase family, was reported to be a strong activator of NCC/NKCC2 when assayed in Xenopus oocytes, suggesting that WNK3 also plays a major role in regulating blood pressure and sodium reabsorption in the kidney. However, it remains to be determined whether WNK3 is in fact involved in the regulation of these transporters in vivo. To clarify this issue, we generated and analyzed WNK3 knockout mice. Surprisingly, phosphorylation and expression of OSR1, SPAK, NKCC2 and NCC did not decrease in knockout mouse kidney under normal and low-salt diets. Similarly, expression of epithelial Na channel and Na/H exchanger 3 were not affected in knockout mice. Na+ and K+ excretion in urine in WNK3 knockout mice was not affected under different salt diets. Blood pressure in WNK3 knockout mice was not lower under normal diet. However, lower blood pressure was observed in WNK3 knockout mice fed low-salt diet. WNK4 and WNK1 expression was slightly elevated in the knockout mice under low-salt diet, suggesting compensation for WNK3 knockout by these WNKs. Thus, WNK3 may have some role in the WNK-OSR1/SPAK-NCC/NKCC2 signal cascade in the kidney, but its contribution to total WNK kinase activity may be minimal.
机译：已显示WNK1和WNK4激酶基因中的突变会导致人类遗传性高血压疾病，即假性醛固酮增多症II型（PHAII）。我们先前发现WNK激酶磷酸化并激活OSR1 / SPAK激酶，后者调节肾脏SLC12A家族转运蛋白（如NKCC2和NCC），并阐明该级联的组成型激活会导致PHAII。据报道，在非洲爪蟾卵母细胞中进行测定时，WNK3是WNK激酶家族的另一个成员，它是NCC / NKCC2的强激活剂，表明WNK3在调节血压和肾脏钠的重吸收中也起着重要作用。但是，WNK3是否实际上参与体内这些转运蛋白的调节尚待确定。为了澄清这个问题，我们生成并分析了WNK3基因敲除小鼠。出乎意料的是，正常和低盐饮食下的敲除小鼠肾脏中，OSR1，SPAK，NKCC2和NCC的磷酸化和表达均未降低。类似地，在敲除小鼠中上皮Na通道和Na / H交换子3的表达不受影响。在不同的盐饮食下，WNK3基因敲除小鼠尿液中的Na +和K +排泄不受影响。在正常饮食下，WNK3基因敲除小鼠的血压并没有降低。但是，在低盐饮食喂养的WNK3基因敲除小鼠中观察到较低的血压。在低盐饮食下，基因敲除小鼠中的WNK4和WNK1表达略有升高，表明这些WNK对WNK3基因敲除的补偿。因此，WNK3可能在肾脏的WNK-OSR1 / SPAK-NCC / NKCC2信号级联反应中具有一定作用，但对总WNK激酶活性的贡献可能很小。

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