Mutation of an anti‐aging gene klotho causes hypertension via upregulation of plasma aldosterone levels

Abstract

Klotho is a recently discovered anti‐aging gene. The purpose of this experiment is to assess if klotho deficiency affects blood pressure. Interestingly, klotho (+/−) mice demonstrated a significant and persistent increase in blood pressure starting form 3–4 months of age, indicating that klotho deficiency causes hypertension. Plasma level of aldosterone was elevated in KL(+/−) mice. Two groups of KL(+/−) mice and 2 groups of wild‐type mice were used. When BP was elevated in KL(+/−) mice, 1 group of KL (+/−) mice and 1 group of WT mice were treated with aldosterone receptor blocker, eplerenone (6 mg/kg/day), while the remaining groups received DMSO and serve as controls. Eplerenone decreased hypertension to the control level. Eplerenone also abolished KL deficiency‐induced kidney damage (glomerulus collapse, fibrosis). Klotho deficiency causes renal inflammation as evidenced by significant increases in inflammatory cytokines (IL‐6, TNFα and MCP‐1) and T cell and macrophage infiltration in kidneys of KL (+/−) mice. Eplerenone significantly attenuated KL deficiency‐induced inflammation. Notably, NCC and Sgk1 levels were increased in kidneys in KL(+/−) mice, which could be abolished by eplerenone. It is concluded that KL deficiency caused hypertension via increasing plasma aldosterone levels which led to inflammation and upregulation of NCC signaling in kidneys.