Abstract 17793: Mutation of Anti-aging Gene Klotho Causes Hypertension via Upregulation of CYP11B2 Expression and Aldosterone Syhthesis
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 study is to assess how KL deficiency may affect blood pressure (BP).
Methods & Results: Heterozygeous KL mutant mice (+/-) showed spontaneous and persistent elevation of BP, indicating that KL is essential to the maintenance of normal BP. Plasma level of aldosterone was increased which concurred with elevation of BP in KL(+/-) mice. Blockade of aldosterone actions by eplerenone (6 mg/kg/day, IP) decreased BP of KL(+/-) mice to the control level and attenuated kidney damage, suggesting that upregulation of aldosterone synthesis is responsible for KL deficiency-induced hypertension. Protein expression of CYP11B2, a key enzyme for aldosterone synthesis, was upregulated in adrenal cortex of KL(+/-) mice. The immunofluorescence analysis showed that klotho and CYP11B2 protein were co-localized in adrenal zona glomerulosa cells. Silencing of klotho upregulated CYP11B2 expression while overexpression of klotho downregulated CYP11B2 expression in adrenocortical cells (human NCl H295R), indicating that klotho regulates CYP11B2 protein expression. Interestingly, silencing of klotho decreased expression of SF1 (negative transcription factor of CYP11B2 expression) but increased phosphorylation of ATF2 (positive transcription factor of CYP11B2 expression). These results suggest that klotho deficiency altered transcription factors leading to upregulation of CYP11B2 expression.
Conclusions: KL deficiency causes hypertension via upregulating CYP11B2 expression and aldosterone syhthesis. This study reveals a novel role of klotho in the regulation of CYP11B2 expression.
Author Disclosures: X. Zhou: None. Y. Wang: None. H. Lei: None.
- © 2014 by American Heart Association, Inc.