Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-0034, Japan.
Clin Exp Nephrol. 2012 Aug;16(4):530-8. doi: 10.1007/s10157-012-0590-x.
We found that a mechanism of hypertension in pseudohypoaldosteronism type II (PHAII) caused by a WNK4 missense mutation (D561A) was activation of the WNK-OSR1/SPAK-NCC signal cascade. However, the pathogenic effect of intronic deletions in WNK1 genes also observed in PHAII patients remains unclear. To understand the pathophysiological roles of WNK1 in vivo, WNK1(+/-)mice have been analyzed, because homozygous WNK1 knockout is embryonic lethal. Although WNK1(+/-) mice have been reported to have hypotension, detailed analyses of the WNK signal cascade in the kidney and other organs of WNK1(+/-) mice have not been performed.
We assess the effect of heterozygous deletion of WNK1 on the WNK-OSR1/SPAK-NCC/NKCC1/NKCC2 signal cascade in the kidney and blood vessels.
Contrary to the previous report, the blood pressure of WNK1(+/-) mice was not decreased, even under a low-salt diet. Under a WNK4(D561A/+) background, the heterozygous deletion of the WNK1 gene did not reduce the high blood pressure either. We then evaluated the phosphorylation status of OSR1, SPAK, NCC, NKCC1, and NKCC2 in the kidney, but no significant decrease in the phosphorylation was observed in WNK1(+/-) mice or WNK1(+/-)WNK4(D561A/+) mice. In contrast, a significant decrease in NKCC1 phosphorylation in the aorta and a decreased pressure-induced myogenic response in the mesenteric arteries were observed in WNK1(+/-) mice.
The contribution of WNK1 to total WNK kinase activity in the kidney may be small, but that WNK1 may play a substantial role in the regulation of blood pressure in the arteries.
我们发现假性醛固酮增多症 II 型（PHAII）中由 WNK4 错义突变（D561A）引起的高血压机制是 WNK-OSR1/SPAK-NCC 信号级联的激活。然而，在 PHAII 患者中观察到的 WNK1 基因内含子缺失的致病效应仍不清楚。为了了解 WNK1 在体内的病理生理作用，我们分析了 WNK1(+/-) 小鼠，因为 WNK1 纯合子缺失是胚胎致死的。尽管已有报道称 WNK1(+/-) 小鼠存在低血压，但尚未对 WNK1(+/-) 小鼠肾脏和其他器官中的 WNK 信号级联进行详细分析。
我们评估了 WNK1 杂合缺失对肾脏和血管中 WNK-OSR1/SPAK-NCC/NKCC1/NKCC2 信号级联的影响。
与之前的报道相反，WNK1(+/-) 小鼠的血压并未降低，即使在低盐饮食下也是如此。在 WNK4(D561A/+) 背景下，WNK1 基因的杂合缺失也没有降低高血压。然后，我们评估了肾脏中 OSR1、SPAK、NCC、NKCC1 和 NKCC2 的磷酸化状态，但在 WNK1(+/-) 小鼠或 WNK1(+/-)WNK4(D561A/+) 小鼠中没有观察到磷酸化明显降低。相反，在 WNK1(+/-) 小鼠中观察到主动脉中 NKCC1 磷酸化显著降低和肠系膜动脉压力诱导的肌源性反应降低。
WNK1 在肾脏中总 WNK 激酶活性中的贡献可能较小，但 WNK1 可能在调节动脉血压方面发挥重要作用。
