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.).
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.)
J Pharmacol Exp Ther. 2014 Aug;350(2):243-56. doi: 10.1124/jpet.113.212076. Epub 2014 May 15.
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.
我们最近的研究表明，阻断 I 类/II 类组蛋白去乙酰化酶（HDACs）可抑制肾间质成纤维细胞的激活和增殖，减轻肾纤维化的发展。然而，III 类 HDAC，特别是 SIRT1 和 SIRT2（SIRT1 和 SIRT2）的抑制作用对肾纤维化的影响仍不清楚。在这里，我们证明 SIRT1 和 SIRT2 均在培养的肾间质成纤维细胞（NRK-49F）中表达。NRK-49F 暴露于 SIRT1/2 的选择性抑制剂 sirtinol 或 SIRT1 的抑制剂 EX527（6-氯-2,3,4,9-四氢-1H-咔唑-1-甲酰胺）会导致成纤维细胞激活标志物（α-平滑肌肌动蛋白、纤维连接蛋白和 I 型胶原）的表达以及增殖标志物（增殖细胞核抗原、细胞周期蛋白 D1、细胞周期蛋白 E）的表达呈剂量和时间依赖性降低。用 SIRT2 抑制剂 AGK2（2-氰基-3-[5-（2,5-二氯苯基）-2-呋喃基]-N-5-喹啉基-2-丙烯酰胺）处理也剂量和时间依赖性地抑制肾成纤维细胞的激活，并且在较小程度上抑制细胞增殖。此外，用小干扰 RNA 沉默 SIRT1 或 SIRT2 也表现出类似的抑制作用。在梗阻性肾病的小鼠模型中，sirtinol 的给药减轻了胶原蛋白纤维的沉积，并减少了损伤肾脏中 α-平滑肌肌动蛋白、I 型胶原和纤维连接蛋白的表达。SIRT1/2 抑制介导的抗纤维化作用与表皮生长因子受体（EGFR）、血小板衍生生长因子受体-β（PDGFRβ）和信号转导和转录激活因子 3 的去磷酸化有关。因此，SIRT1/2 活性可能通过激活至少 EGFR 和 PDGFRβ 信号通路促进肾成纤维细胞的激活和增殖以及肾纤维化的发生。阻断 SIRT1/2 激活可能具有治疗慢性肾脏病的治疗潜力。
