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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

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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 8

Klotho supplement normalizes augmented response of RBF to Ang II and U46119 in salt-loaded aged WT mice and heterozygous KL-KO mice.

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Klotho supplement normalizes augmented response of RBF to Ang II and U46...
(A) Percent changes in RBF with the intra-arterial injection of Ang II (left) or U46619 (right) in young WT mice with NS or HS diet. Bar graphs show the area under the curve of changes in RBF compared with the baseline. For Ang II, n = 6 each; for U46619, n = 5 each. N.S., not significant. (B) Percent changes in RBF upon intra-arterial injection of Ang II (left) or U46619 (right) in aged WT mice receiving NS, HS, or HS diet + Klotho supplementation. Bar graphs show the area under the curve of changes in RBF relative to the baseline. n = 4 each. *P < 0.05 vs. HS diet–fed mice. (C) Percent changes in RBF upon intra-arterial injection of Ang II (left) or U46619 (right) in KL-KO mice with NS diet, HS diet, or HS diet + KL. Bar graphs show area under the curve of changes in RBF relative to the baseline. Ang II, n = 6 each; U46619, n = 6 (NS diet), n = 5 (HS diet), and n = 5 (HS diet + KL). *P < 0.05 vs. HS diet–fed mice. Data are means ± SEM. Unpaired t tests were performed on comparisons between 2 groups. For multiple comparisons, statistical analysis was performed by Tukey-Kramer post hoc test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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