Blocking sirtuin 1 and 2 inhibits renal interstitial fibroblast activation and attenuates renal interstitial fibrosis in obstructive nephropathy.
Our recent studies revealed that blocking class I/II histone deacetylases (HDACs) inhibits renal interstitial fibroblast activation and proliferation and alleviates development of renal fibrosis. However, the effect of class III HDAC, particularly sirtuin 1 and 2 (SIRT1 and SIRT2), inhibition on renal fibrogenesis remains elusive. Here, we demonstrate that both SIRT1 and SIRT2 were expressed in cultured renal interstitial fibroblasts (NRK-49F). Exposure of NRK-49F to sirtinol, a selective inhibitor of SIRT1/2, or EX527 (6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide), an inhibitor for SIRT1, resulted in reduced expression of fibroblast activation markers (α-smooth muscle actin, fibronectin, and collagen I) as well as proliferation markers (proliferating cell nuclear antigen, cyclin D1, cyclin E) in dose- and time-dependent manners. Treatment with a SIRT2 inhibitor, AGK2 (2-cyano-3-[5-(2,5-dichlorophenyl)-2-furanyl]-N-5-quinolinyl-2-propenamide), also dose- and time-dependently inhibited renal fibroblast activation and, to a lesser extent, cell proliferation. Furthermore, silencing of either SIRT1 or SIRT2 by small interfering RNA exhibited similar inhibitory effects. In a mouse model of obstructive nephropathy, administration of sirtinol attenuated deposition of collagen fibrils as well as reduced expression of α-smooth muscle actin, collagen I, and fibronectin in the injured kidney. SIRT1/2 inhibition-mediated antifibrotic effects are associated with dephosphorylation of epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor-β (PDGFRβ), and signal transducer and activator of transcription 3. Thus, SIRT1/2 activity may contribute to renal fibroblast activation and proliferation as well as renal fibrogenesis through activation of at least EGFR and PDGFRβ signaling. Blocking SIRT1/2 activation may have therapeutic potential for the treatment of chronic kidney disease.
Department of Medicine, Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island (M.P., X.Z., Y.Y., E.T., R.G., S.Z.); First Affiliated Hospital of Harbin Medical University, Harbin, China (X.Z.); Departments of Nephrology (J.T., S.Z.) and Emergency Medicine (Y.Y.), Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; and Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island (T.C.Z.).
Murugavel
M
Ponnusamy
Department of Medicine, Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island (M.P., X.Z., Y.Y., E.T., R.G., S.Z.); First Affiliated Hospital of Harbin Medical University, Harbin, China (X.Z.); Departments of Nephrology (J.T., S.Z.) and Emergency Medicine (Y.Y.), Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; and Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island (T.C.Z.).
Xiaoxu
X
Zhou
Department of Medicine, Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island (M.P., X.Z., Y.Y., E.T., R.G., S.Z.); First Affiliated Hospital of Harbin Medical University, Harbin, China (X.Z.); Departments of Nephrology (J.T., S.Z.) and Emergency Medicine (Y.Y.), Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; and Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island (T.C.Z.).
Yanli
Y
Yan
Department of Medicine, Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island (M.P., X.Z., Y.Y., E.T., R.G., S.Z.); First Affiliated Hospital of Harbin Medical University, Harbin, China (X.Z.); Departments of Nephrology (J.T., S.Z.) and Emergency Medicine (Y.Y.), Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; and Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island (T.C.Z.).
Jinhua
J
Tang
Department of Medicine, Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island (M.P., X.Z., Y.Y., E.T., R.G., S.Z.); First Affiliated Hospital of Harbin Medical University, Harbin, China (X.Z.); Departments of Nephrology (J.T., S.Z.) and Emergency Medicine (Y.Y.), Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; and Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island (T.C.Z.).
Evelyn
E
Tolbert
Department of Medicine, Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island (M.P., X.Z., Y.Y., E.T., R.G., S.Z.); First Affiliated Hospital of Harbin Medical University, Harbin, China (X.Z.); Departments of Nephrology (J.T., S.Z.) and Emergency Medicine (Y.Y.), Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; and Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island (T.C.Z.).
Ting C
TC
Zhao
Department of Medicine, Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island (M.P., X.Z., Y.Y., E.T., R.G., S.Z.); First Affiliated Hospital of Harbin Medical University, Harbin, China (X.Z.); Departments of Nephrology (J.T., S.Z.) and Emergency Medicine (Y.Y.), Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; and Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island (T.C.Z.).
Rujun
R
Gong
Department of Medicine, Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island (M.P., X.Z., Y.Y., E.T., R.G., S.Z.); First Affiliated Hospital of Harbin Medical University, Harbin, China (X.Z.); Departments of Nephrology (J.T., S.Z.) and Emergency Medicine (Y.Y.), Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; and Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island (T.C.Z.) szhuang@lifespan.org.
Shougang
S
Zhuang
D000199:Actins / Q000032:analysis; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects*; D005355:Fibrosis; D005663:Furans / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009284:Naphthols / Q000494:pharmacology*; D010766:Phosphorylation; D011804:Quinolines / Q000494:pharmacology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy; D050796:STAT3 Transcription Factor / Q000032:analysis; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors*
C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; C521855:AGK2 compound; D000199:Actins; D001549:Benzamides; D002227:Carbazoles; D005663:Furans; D009284:Naphthols; D011804:Quinolines; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C544013:alpha-smooth muscle actin, mouse; C439060:sirtinol; D066246:ErbB Receptors; D020797:Receptor, Platelet-Derived Growth Factor beta; D056564:Sirtuin 1; D056565:Sirtuin 2