title: Resveratrol increases anti-aging Klotho gene expression via the activating transcription factor 3/c-Jun complex-mediated signaling pathway.
abstract: The Klotho gene functions as an aging suppressor gene. Evidence from animal models suggests that induction of Klotho expression may be a potential treatment for age-associated diseases. However, the molecular mechanism involved in regulating renal Klotho gene expression remains unclear. In this study, we determined that resveratrol, a natural polyphenol, induced renal Klotho expression both in vivo and in vitro. In the mouse kidney, resveratrol administration markedly increased both Klotho mRNA and protein expression. In resveratrol-treated NRK-52E cells, increased Klotho expression was accompanied by the upregulation and nuclear translocation of activating transcription factor 3 (ATF3) and c-Jun. ATF3 or c-Jun overexpression enhanced the transcriptional activation of Klotho. Conversely, resveratrol-induced Klotho expression was attenuated in the presence of dominant-negative ATF3 or c-Jun. Coimmunoprecipitation and a chromatin immunoprecipitation assay revealed that ATF3 physically interacted with c-Jun and that the ATF3/c-Jun complex directly bound to the Klotho promoter through ATF3- and AP-1-binding elements. c-Jun cotransfection augmented the effects of ATF3 on Klotho transcription in vitro. Although Sirtuin 1 mRNA expression was induced by resveratrol and involved in regulating Klotho mRNA expression, it was not the primary cause for the aforementioned ATF3/c-Jun pathway. In summary, resveratrol enhances the renal expression of the anti-aging Klotho gene, and the transcriptional factors ATF3 and c-Jun functionally interact and coordinately regulate the resveratrol-mediated transcriptional activation of Klotho.
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Shih-Che
authors.initials: SC
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan; Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Shih-Ming
authors.initials: SM
authors.lastname: Huang
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan; Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Ann
authors.initials: A
authors.lastname: Chen
authors.affiliation: Division of Nephrology, Chang Gung Memorial Hospital, Keelung, Taiwan; School of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chiao-Yin
authors.initials: CY
authors.lastname: Sun
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan; Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Shih-Hua
authors.initials: SH
authors.lastname: Lin
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan; Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Jin-Shuen
authors.initials: JS
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Shu-Ting
authors.initials: ST
authors.lastname: Liu
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan; Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. Electronic address: yujuei@mail2000.com.tw.
authors.forename: Yu-Juei
authors.initials: YJ
authors.lastname: Hsu
mesh_terms: D051700:Activating Transcription Factor 3 / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D005966:Glucuronidase / Q000096:biosynthesis* / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D000090265:Klotho Proteins; D051379:Mice; D012333:RNA, Messenger / Q000096:biosynthesis; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000096:biosynthesis; D013267:Stilbenes / Q000008:administration & dosage*; D018808:Transcription Factor AP-1 / Q000235:genetics
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D012333:RNA, Messenger; D013267:Stilbenes; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases; D005966:Glucuronidase; D000090265:Klotho Proteins; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: Activating transcription factor 3 (ATF3); Anti-aging; Klotho; Resveratrol; c-Jun