title: Testosterone increases renal anti-aging klotho gene expression via the androgen receptor-mediated pathway.
abstract: Gender is known to be associated with longevity and oestrogen administration induced longevity-associated gene expression is one of the potential mechanisms underlying the benefits of oestrogen on lifespan, whereas the role of testosterone in the regulation of longevity-associated gene expressions remains largely unclear. The klotho gene, predominantly expressed in the kidney, has recently been discovered to be an aging suppressor gene. In the present study, we investigated the regulatory effects of testosterone on renal klotho gene expression in vivo and in vitro. In testosterone-administered mouse kidney and NRK-52E cells, increased klotho expression was accompanied by the up-regulation of the nuclear androgen receptor (AR). Overexpression of AR enhanced the expression of klotho mRNA and protein. Conversely, testosterone-induced klotho expression was attenuated in the presence of flutamide, an AR antagonist. A reporter assay and a chromatin immunoprecipitation (ChIP) assay demonstrated that AR directly binds to the klotho promoter via androgen response elements (AREs) which reconfirmed its importance for AR binding via the element mutation. In summary, our study demonstrates that testosterone up-regulates anti-aging klotho together with AR expression in the kidney in vivo and in vitro by recruiting AR on to the AREs of the klotho promoter.
authors.affiliation: *Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, R.O.C.
authors.forename: Shih-Che
authors.initials: SC
authors.lastname: Hsu
authors.forename: Shih-Ming
authors.initials: SM
authors.lastname: Huang
authors.forename: Shih-Hua
authors.initials: SH
authors.lastname: Lin
authors.affiliation: §Graduate Institute of Aerospace and Undersea Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C.
authors.forename: Shuk-Man
authors.initials: SM
authors.lastname: Ka
authors.affiliation: ¶Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C.
authors.forename: Ann
authors.initials: A
authors.lastname: Chen
authors.affiliation: **Department of Nephrology, Mackay Memorial Hospital, Taipei, Taiwan, R.O.C.
authors.forename: Meng-Fu
authors.initials: MF
authors.lastname: Shih
authors.forename: Yu-Juei
authors.initials: YJ
authors.lastname: Hsu
mesh_terms: D000375:Aging / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D004967:Estrogens / Q000378:metabolism; D005485:Flutamide / Q000494:pharmacology; D005786:Gene Expression Regulation; D005966:Glucuronidase / Q000096:biosynthesis*; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D000090265:Klotho Proteins; D008136:Longevity / Q000187:drug effects / Q000235:genetics*; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D011944:Receptors, Androgen / Q000096:biosynthesis*; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013739:Testosterone / Q000008:administration & dosage / Q000378:metabolism
chemical_list: D004967:Estrogens; D012333:RNA, Messenger; D011944:Receptors, Androgen; D013739:Testosterone; D005485:Flutamide; D005966:Glucuronidase; D000090265:Klotho Proteins