title: Sinomenine attenuates renal fibrosis through Nrf2-mediated inhibition of oxidative stress and TGFβ signaling.
abstract: Renal fibrosis is the common feature of chronic kidney disease and mainly mediated by TGFβ-associated pro-fibrogenic signaling, which causes excessive extracellular matrix accumulation and successive loss of kidney functions. Sinomenine (SIN), an alkaloid derived from medicinal herb extensively used in treatment of rheumatoid arthritis and various inflammatory disorders, displays renal protective properties in experimental animals; however its pharmacological potency against renal fibrosis is not explored. In this study we report that SIN possesses strong anti-renal fibrosis functions in kidney cell and in mouse fibrotic kidney. SIN beneficially modulated the pro-fibrogenic protein expression in TGFβ-treated kidney cells and attenuated the renal fibrotic pathogenesis incurred by unilateral ureteral obstruction (UUO), which correlated with its activation of Nrf2 signaling - the key defender against oxidative stress with anti-fibrotic potentials. Further investigation on its regulation of Nrf2 downstream events revealed that SIN significantly balanced oxidative stress via improving the expression and activity of anti-oxidant and detoxifying enzymes, and interrupted the pro-fibrogenic signaling of TGFβ/Smad and Wnt/β-catenin. Even more impressively SIN achieved its anti-fibrotic activities in an Nrf2-dependent manner, suggesting that SIN regulation of Nrf2-associated anti-fibrotic activities constitutes a critical component of SIN's renoprotective functions. Collectively our studies have demonstrated a novel anti-fibrotic property of SIN and its upstream events and provided a molecular basis for SIN's potential applications in treatment of renal fibrosis-associated kidney disorders.
authors.affiliation: School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Qin
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing 210093, China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Yin
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing 210093, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing 210093, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing 210093, China.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, China. Electronic address: hfj@cpu.edu.cn.
authors.forename: Fengjie
authors.initials: F
authors.lastname: Huang
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing 210093, China. Electronic address: wangsencao@nju.edu.cn.
authors.forename: Wangsen
authors.initials: W
authors.lastname: Cao
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D018501:Antirheumatic Agents / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism; D005355:Fibrosis; D005979:Glutathione Peroxidase / Q000378:metabolism; D057809:HEK293 Cells; D007674:Kidney Diseases / Q000473:pathology; D009019:Morphinans / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism
chemical_list: D018501:Antirheumatic Agents; D002374:Catalase; D005979:Glutathione Peroxidase; D009019:Morphinans; C009271:sinomenine; D013482:Superoxide Dismutase; D053773:Transforming Growth Factor beta1; D051267:NF-E2-Related Factor 2
keywords: Nrf2; Oxidative stress; Renal fibrosis; Sinomenine; TGFβ