Salt causes aging-associated hypertension via vascular Wnt5a under Klotho deficiency
Salt causes aging-associated hypertension via vascular Wnt5a under Klotho deficiency
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DOI：
10.1172/jci134431
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发表时间：
2020-08-03
影响因子：
15.9
通讯作者：
Fujita, Toshiro
中科院分区：
文献类型：
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作者：
Kawarazaki, Wakako;Mizuno, Risuke;Fujita, Toshiro
由于饮食盐对血压的易感性升高，衰老与高血压的高患病率相关，但其机制尚不清楚。抗衰老因子Klotho的血清水平随着年龄的增长而下降。我们发现，高盐（HS）增加了老年小鼠和年轻杂合kloho基因敲除小鼠的血压，并与血管中Wnt5a和p-MYPT1的表达增加有关，这表明RhoA的活性。除了Wnt抑制剂LGK974和Wnt5a拮抗剂BoxS外，Klotho补充剂还能抑制hs诱导的血压升高，与Rho激酶抑制剂法舒地尔类似，这与两组小鼠p-MYPT1表达降低有关。在培养的血管平滑肌细胞中，Wnt5a和血管紧张素II （Ang II）增加了p-MYPT1的表达，但用siRNA敲低Wnt5a可消除Ang II诱导的p-MYPT1上调，这表明Wnt5a对于Ang II诱导的Rho/ROCK激活是不可或缺的。值得注意的是，Klotho抑制Wnt5a-和Ang ii诱导的p-MYPT1上调。与此一致的是，Klotho补充剂改善了hs诱导的肾血流量减少（RBF）对动脉内输注Ang II和血栓素A(2)类似物U46619的增强反应，后者激活了两组小鼠的RhoA，并与抑制血压升高有关，这表明RBF对Ang II的异常反应有助于hs诱导的血压升高。因此，Klotho缺乏症通过血管非典型Wnt5a/RhoA激活成为衰老相关盐敏感性高血压的基础。
Aging is associated with a high prevalence of hypertension due to elevated susceptibility of BP to dietary salt, but its mechanism is unknown. Serum levels of Klotho, an anti-aging factor, decline with age. We found that high salt (HS) increased BP in aged mice and young heterozygous Klotho-knockout mice and was associated with increased vascular expression of Wnt5a and p-MYPT1, which indicate RhoA activity. Not only the Wnt inhibitor LGK974 and the Wnt5a antagonist BoxS but Klotho supplementation inhibits HS-induced BP elevation, similarly to the Rho kinase inhibitor fasudil, associated with reduced p-MYPT1 expression in both groups of mice. In cultured vascular smooth muscle cells, Wnt5a and angiotensin II (Ang II) increased p-MYPT1 expression but knockdown of Wnt5a with siRNA abolished Ang II-induced upregulation of p-MYPT1, indicating that Wnt5a is indispensable for Ang II-induced Rho/ROCK activation. Notably, Klotho inhibited Wnt5a- and Ang II-induced upregulation of p-MYPT1. Consistently, Klotho supplementation ameliorated HS-induced augmentation of reduced renal blood flow (RBF) response to intra-arterial infusion of Ang II and the thromboxane A(2) analog U46619, which activated RhoA in both groups of mice and were associated with the inhibition of BP elevation, suggesting that abnormal response of RBF to Ang II contributes to HS-induced BP elevation. Thus, Klotho deficiency underlies aging-associated salt-sensitive hypertension through vascular non-canonical Wnt5a/RhoA activation.