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Anti‐aging gene klotho deficiency causes arterial stiffness via activation of aldosterone receptors and increased autophagy (880.6)
Author(s) -
Chen Kai,
Zhou Xiaoli,
Sun Zhongjie
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.880.6
Subject(s) - klotho , eplerenone , medicine , endocrinology , arterial stiffness , aldosterone , mineralocorticoid receptor , receptor , downregulation and upregulation , chemistry , kidney , blood pressure , biochemistry , gene
Background & Objective. The prevalence of arterial stiffness increases with age while the klotho level decreases with age. Klotho deficiency increases circulating aldosterone levels. The objective of this study was to test the hypothesis that klotho deficiency causes arterial stiffness via activation of aldosterone receptors. Methods & Results. Klotho heterozygous (klotho +/‐ ) mice (1.5 years) and their wild type (WT) littermates were treated with or without aldosterone receptor blocker eplerenone (6 mg/kg/day, IP) for 3 weeks. Pulse wave velocity (PWV), a direct measure of arterial stiffness, was significantly increased in klotho +/‐ mice, suggesting that klotho deficiency causes arterial stiffening. Eplerenone abolished klotho deficiency‐induced arterial stiffening. Arterial stiffness was associated with increased collagen and decreased elastin contents in the media of aortas. Mechanistically, klotho deficiency increased arterial MMP2, MMP9 and TGFβ expression, which were blocked by eplerenone. In addition, klotho deficiency induced arterial autophagy and increased scleraxis (a transcription factor for collagen synthesis) expression, which was reversed by eplerenone. Conclusion. Klotho deficiency causes arterial stiffening via activation of aldosterone receptors which leads to upregulation of MMP2, MMP9, TGFβ, and scleraxis and increased autophagy. Grant Funding Source : Supported by HL105302 and HL 102074.