title: Antiaging Gene Klotho Regulates Adrenal CYP11B2 Expression and Aldosterone Synthesis.
abstract: Deficiency of the antiaging gene Klotho (KL) induces renal damage and hypertension through unknown mechanisms. In this study, we assessed whether KL regulates expression of CYP11B2, a key rate-limiting enzyme in aldosterone synthesis, in adrenal glands. We found that haplodeficiency of KL(+/-) in mice increased the plasma level of aldosterone by 16 weeks of age, which coincided with spontaneous and persistent elevation of BP. Blockade of aldosterone actions by eplerenone reversed KL deficiency-induced hypertension and attenuated the kidney damage. Protein expression of CYP11B2 was upregulated in adrenal cortex of KL(+/-) mice. KL and CYP11B2 proteins colocalized in adrenal zona glomerulosa cells. Silencing of KL upregulated and overexpression of KL downregulated CYP11B2 expression in human adrenocortical cells. Notably, silencing of KL decreased expression of SF-1, a negative transcription factor of CYP11B2, but increased phosphorylation of ATF2, a positive transcription factor of CYP11B2, which may contribute to upregulation of CYP11B2 expression. Therefore, these results show that KL regulates adrenal CYP11B2 expression. KL deficiency-induced spontaneous hypertension and kidney damage may be partially attributed to the upregulation of CYP11B2 expression and aldosterone synthesis.
authors.affiliation: Department of Cardiology, First Affiliated Hospital, Chongqing Medical University, Chongqing, China; and Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Mariano
authors.initials: M
authors.lastname: Schuman
authors.affiliation: Department of Cardiology, First Affiliated Hospital, Chongqing Medical University, Chongqing, China; and.
authors.forename: Han
authors.initials: H
authors.lastname: Lei
authors.affiliation: Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma Zhongjie-Sun@ouhsc.edu.
authors.forename: Zhongjie
authors.initials: Z
authors.lastname: Sun
mesh_terms: D000302:Adrenal Cortex / Q000378:metabolism*; D000450:Aldosterone / Q000096:biosynthesis*; D000818:Animals; D019405:Cytochrome P-450 CYP11B2 / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D005966:Glucuronidase / Q000235:genetics* / Q000502:physiology; D006801:Humans; D000090265:Klotho Proteins; D051379:Mice; D015854:Up-Regulation
chemical_list: D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: BP; aldosterone; hypertension; immune complexes; kidney dysfunction; macrophages