title: Sirtuin 1 Activation Reduces Transforming Growth Factor-β1-Induced Fibrogenesis and Affords Organ Protection in a Model of Progressive, Experimental Kidney and Associated Cardiac Disease.
abstract: Most forms of chronic, progressive kidney disease are characterized by fibrosis whereby the prototypical prosclerotic growth factor, transforming growth factor β (TGF-β), is thought to play a pivotal role. With the recent understanding that TGF-β's canonical signaling pathway may be modified by acetylation as well as phosphorylation, we explored the role of the NAD+-dependent lysine deacetylase, sirtuin 1 (SIRT1) in fibrogenesis in the cell culture, animal model, and human settings. In vitro, the increase in collagen production that results from TGF-β1 stimulation was ameliorated by the allosteric modifier of Sirt1 deacetylase, SRT3025, in association with a reduction in Smad3 reporter activity. In the remnant kidney model (subtotally or 5/6 nephrectomized rats) that develops progressive kidney disease in association with TGF-β overexpression, administration of SRT3025 attenuated glomerular filtration rate decline and proteinuria without affecting blood pressure. Glomerulosclerosis and tubulointerstitial fibrosis were similarly reduced with Sirt1 activation as were cardiac structure and function in this rodent model of primary kidney and secondary cardiac disease. Relating these findings to the human setting, we noted a reduction in SIRT1 mRNA in kidney biopsies obtained from individuals with focal glomerulosclerosis. Together these studies highlight the potential of SIRT1 activation as a therapeutic strategy in progressive, fibrotic kidney disease.
authors.affiliation: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Connelly
authors.affiliation: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Kerri
authors.initials: K
authors.lastname: Thai
authors.affiliation: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Xinglin
authors.initials: X
authors.lastname: Wu
authors.affiliation: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Andras
authors.initials: A
authors.lastname: Kapus
authors.affiliation: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Kepecs
authors.affiliation: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada. Electronic address: richard.gilbert@utoronto.ca.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Gilbert
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001706:Biopsy; D001794:Blood Pressure / Q000187:drug effects; D003094:Collagen / Q000096:biosynthesis; D004195:Disease Models, Animal; D018450:Disease Progression; D005247:Feeding Behavior / Q000187:drug effects; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D005923:Glomerulosclerosis, Focal Segmental / Q000473:pathology / Q000503:physiopathology; D057809:HEK293 Cells; D006331:Heart Diseases / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D006334:Heart Function Tests / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D007677:Kidney Function Tests; D011392:Proline / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011916:Rats, Inbred F344; D051436:Renal Insufficiency, Chronic / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D000813:Anilides; D012333:RNA, Messenger; C000601293:SRT3025; D051900:Smad3 Protein; D013844:Thiazoles; D053773:Transforming Growth Factor beta1; D003094:Collagen; D011392:Proline; D056564:Sirtuin 1