S-18-6: SALT AND AGE-RELATED HYPERTENSION

Abstract

Hypertension is the greatest risk factor for cardiovascular disease and stroke, and its incidence increases with age. Clinical studies have shown that salt intake is involved in the development of age-related hypertension and that salt sensitivity of blood pressure (BP) increases with age, but the mechanism was unknown. On the other hand, it was reported that circulating Klotho level, an anti-aging factor protein, decreased with age, and there was an inverse relationship between circulating Klotho and mean BP changes after saline infusion. We hypothesized that the decrease in circulating Klotho levels might be involved in the increase in salt sensitivity of BP with aging. We found that circulating Klotho significantly decreased in aged mice and Klotho heterozygous knockout (KO) mice than in young wild-type mice. They showed salt-sensitive hypertension unlike young wild-type mice, suggesting that a decrease in circulating Klotho was involved in the pathogenesis of salt-sensitive hypertension in aged mice. In both aged mice and Klotho heterozygous KO mice, it was revealed that vascular Wnt5a-RhoA pathway was activated and vasoconstriction was enhanced during high salt intake, resulting in hypertension. We also demonstrated that Klotho supplementation and Wnt and Rho kinase inhibitors significantly suppressed the BP elevation during high salt intake in these mice. Furthermore, we found that Wnt5a was essential for the activation of RhoA by Angiotensin II, an important agent in the formation of hypertension. Since increased vascular resistance of the renal arteries and decreased renal blood flow are involved in the pathogenesis of salt-sensitive hypertension. We analyzed the effects of Angiotensin II and RhoA stimulators to the renal arteries of high-salt fed aged mice and Klotho heterozygous KO mice. Marked vasoconstriction of the renal arteries and decrease in renal blood flow with BP elevation were observed, while responses were less in young mice. Augmented responses observed in aged mice and Klotho heterozygous KO mice were normalized by Klotho supplementation. These findings suggest that in aged mice with low circulating Klotho, salt intake causes activation of the vascular Wnt5a-RhoA pathway, resulting in increased contraction of the renal arteries as well as peripheral blood vessels, which reduces renal blood flow and eventually caused hypertension. We suggest that reducing salt consumption is highly important and lifestyle habits preserving adequate levels of Klotho are useful in the prevention of age-related hypertension. Wnt and Rho inhibitors may be new treatment options. Therapeutic development focusing on the unique background of aging may be applied to other age-related diseases.