Abstract 67: Anti-aging Gene Klotho Deficiency Causes Hypertension Via Upregulation of CYP11B2 Expression and Aldosterone Synthesis

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Background - Klotho (KL) is a recently discovered anti-aging gene. Genetic mutation of KL expedites the aging process and shortens lifespan while overexpression of KL slows down the aging process and extends lifespan. The purpose of this experiment is to assess if KL deficiency affects blood pressure (BP).

Methods & Results - KL mutant heterozygeous (+/-) mice showed significant and persistent elevation of BP, demonstrating for the first time that half klotho deficiency causes hypertension. It is noticed that plasma level of aldosterone was elevated and that protein expression of CYP11B2 (key enzyme of aldosterone synthesis) in adrenal cortex was increased in KL(+/-) mice, indicating that KL deficiency upregulates aldosterone synthesis. Blockade of aldosterone receptors by eplerenone (6 mg/kg/day) decreased hypertension of KL(+/-) mice to the control level within one week, suggesting that upregulation of aldosterone levels may play a critical role in KL deficiency-induced hypertension. Indeed, the aldosterone signaling (SGK1, NCC and ATP-β) were increased in kidneys of KL(+/-) mice. In addition, half KL deficiency increased renal inflammation as evidenced by upregulated inflammatory factors (IL-6, TNFα, osteopontin and MCP-1) and increased infiltration of T cells and macrophages in kidneys of KL(+/-) mice. Half KL deficiency led to renal functional impairment (increased plasma creatinine and urea and urine albumin) and structural damage (glomerulus collapse, tubule fibrosis). Blockade of aldosterone receptors attenuated KL deficiency-induced renal inflammation and damage.

Conclusions - KL is essential to the maintenance of normal BP. KL deficiency caused hypertension and kidney damage via upregulating aldosterone levels and consequently increasing inflammation and SGK1 and NCC signaling in kidneys.

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