Salt causes aging-associated hypertension via vascular Wnt5a under Klotho deficiency
Wakako Kawarazaki, … , Takeshi Marumo, Toshiro Fujita
Wakako Kawarazaki, … , Takeshi Marumo, Toshiro Fujita
Published June 29, 2020
Citation Information: J Clin Invest. 2020;130(8):4152-4166. https://doi.org/10.1172/JCI134431.
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Research Article Nephrology Vascular biology Article has an altmetric score of 44

Salt causes aging-associated hypertension via vascular Wnt5a under Klotho deficiency

Abstract

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 Box5 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 A2 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.

Authors

Wakako Kawarazaki, Risuke Mizuno, Mitsuhiro Nishimoto, Nobuhiro Ayuzawa, Daigoro Hirohama, Kohei Ueda, Fumiko Kawakami-Mori, Shigeyoshi Oba, Takeshi Marumo, Toshiro Fujita

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Figure 4

Aortic active β-catenin expression increases in aged WT mice and is enhanced by HS diet.

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Aortic active β-catenin expression increases in aged WT mice and is enha...
Not β-catenin inhibitor but Wnt inhibitor suppressed salt-induced hypertension and vascular p-MYPT1 expression in HS diet–fed aged WT and heterozygous KL-KO mice. (A) Active β-catenin expression in the aortae of aged WT (left) and KL-KO mice (right) fed NS diet or HS diet, relative to the level in young WT mice. n = 9. *P < 0.05 vs. young WT, aged WT, or KL-KO fed NS diet. (B) Effects of LGK974 (blue) and ICG-001 (orange) on circadian changes in MBP in aged WT (left) and KL-KO mice fed HS diet (right). Right panels show average MBP. n = 4 each. *P < 0.05 vs. HS diet + LGK. (C and D) Effects of ICG-001 (C) and LGK974 (D) on p-MYPT1 expression stimulated by U46619 in the iliac arteries of aged WT and KL-KO mice fed HS diet. (C) Aged WT fed HS diet, n = 7; aged WT fed HS diet + ICG, n = 8; KL-KO fed HS diet and KL-KO fed HS diet + ICG, n = 6 each. (D) Aged WT fed HS diet and aged WT fed HS + LGK, n = 7 each. KL-KO fed HS diet and KL-KO fed HS diet + LGK, n = 8 each. *P < 0.05 vs. HS. Data are means ± SEM. Unpaired t tests were used for comparisons between 2 groups. For multiple comparisons, statistical analysis was performed using the Tukey-Kramer post hoc test. N.S., not significant.