title: Activation of Sirtuin-1 Promotes Renal Fibroblast Activation and Aggravates Renal Fibrogenesis.
abstract: Although activation of sirtuin-1 (SIRT1) has been shown to protect the kidney from acute injury, its role in renal fibrosis remains controversial since both inhibition and activation of SIRT1 have been reported to attenuate renal fibrosis. To resolve this conflict, we further examined the effect of SIRT1 activators on the activation of renal interstitial fibroblasts and development of renal fibrosis in vivo and in vitro. In a murine model of renal fibrosis induced by unilateral ureteral obstruction, administration of SRT1720 (N-[2-[3-(piperazin-1-ylmethyl)imidazo[2,1-b][1,3]thiazol-6-yl]phenyl]quinoxaline-2-carboxamide), a potent activator of SIRT1, accelerated deposition of collagen fibrils and increased expression of fibroblast activation markers (α-smooth muscle actin [α-SMA], collagen I, and fibronectin) in the obstructive kidney of mice. In cultured rat renal interstitial fibroblasts (NRK-49F), exposure of cells to SRT1720 or YK-3-237 (B-[2-methoxy-5-[(1E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propen-1-yl]phenyl]-boronic acid), another SIRT1 activator, also resulted in enhanced expression of α-SMA and fibronectin. Mechanistic studies showed that augmentation of renal fibrogenesis by SRT1720 is associated with elevated phosphorylation of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor β (PDGFRβ). SRT1720 treatment also increased the phosphorylation of signal transducer and activator of transcription 3 and protein kinase B in the fibrotic kidney and NRK-49F cells. However, SRT1720 treatment did not affect expression of proliferating cell nuclear protein, a proliferation marker and activation of extracellular signal regulated kinase 1/2 in vitro and in vivo. These results indicate that SIRT1-activating compounds can provoke renal fibrogenesis through a mechanism involved in the activation of EGFR and PDGFR signaling pathways and suggest that long-term use of SIRT1 activators risks the development and progression of chronic kidney disease.
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island (M.P., M.A.Z., X.Z., E.T., G.B., S.Z.); Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island (T.C.Z.); and Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China (S.Z.).
authors.forename: Murugavel
authors.initials: M
authors.lastname: Ponnusamy
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island (M.P., M.A.Z., X.Z., E.T., G.B., S.Z.); Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island (T.C.Z.); and Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China (S.Z.).
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Zhuang
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island (M.P., M.A.Z., X.Z., E.T., G.B., S.Z.); Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island (T.C.Z.); and Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China (S.Z.).
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island (M.P., M.A.Z., X.Z., E.T., G.B., S.Z.); Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island (T.C.Z.); and Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China (S.Z.).
authors.forename: Evelyn
authors.initials: E
authors.lastname: Tolbert
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island (M.P., M.A.Z., X.Z., E.T., G.B., S.Z.); Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island (T.C.Z.); and Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China (S.Z.).
authors.forename: George
authors.initials: G
authors.lastname: Bayliss
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island (M.P., M.A.Z., X.Z., E.T., G.B., S.Z.); Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island (T.C.Z.); and Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China (S.Z.).
authors.forename: Ting C
authors.initials: TC
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island (M.P., M.A.Z., X.Z., E.T., G.B., S.Z.); Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island (T.C.Z.); and Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China (S.Z.) szhuang@lifespan.org.
authors.forename: Shougang
authors.initials: S
authors.lastname: Zhuang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: C470545:Sirt1 protein, mouse; D056564:Sirtuin 1