title: Sinomenine activation of Nrf2 signaling prevents hyperactive inflammation and kidney injury in a mouse model of obstructive nephropathy.
abstract: Sinomenine is originally derived from medicinal herb and used preferentially in treatment of rheumatoid diseases in Far East regions. SIN has strong anti-inflammatory and immune-regulatory properties, acting mainly through inhibiting NF-kB signaling. Although the upstream target through which SIN affects NF-kB activity is unknown, evidence suggests that SIN might regulate inflammation through Nrf2 signaling. In this study we explored the role of Nrf2 in mediating SIN's anti-inflammation and kidney protection in a mouse model of obstructive nephropathy. We found that SIN is an activator of Nrf2 signaling. It markedly increased Nrf2 protein level, Nrf2 nuclear translocation, Nef2 transcription capacity, and the downstream protein expression. We further demonstrated that SIN activation of Nrf2 is likely due to its repression of the Nrf2 inhibitor Keap1 since it drastically reduced Keap1 protein through the PKC-sensitive ubiquitination-proteasomal degradation. SIN treatment of nephropathy mice effectively reduced the kidney damage and inflammatory responses, balanced renal oxidative stress, and improved the pathological protein expression in an Nrf2 dependent manner. In addition, SIN also Nrf2-dependently modulated macrophage M1/M2 polarization and inhibited the IkBα phosphorylation and NF-kB nuclear translocation, hence revealing an important upstream event that contributed to its anti-inflammation and tissue protection. Taken together our study has identified a novel pathway through which SIN exerts its anti-inflammation and renal protective functions, and provided a molecular basis for SIN potential applications in the treatment of kidney and other inflammatory disorders.
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing 210093, China; School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, China. Electronic address: tim_chin@sina.com.
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. Electronic address: rhdu@nju.edu.cn.
authors.forename: Ronghui
authors.initials: R
authors.lastname: Du
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: sswwyql@163.com.
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. Electronic address: yangjuni0704@163.com.
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. Electronic address: shfdmc2010@163.com.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Qin
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: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000293:injuries; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009019:Morphinans / Q000008:administration & dosage*; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D009019:Morphinans; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; C009271:sinomenine; D051547:Heme Oxygenase-1
keywords: HO-1; Inflammation; Macrophages; NF-kB; Nrf2; Renoprotection; Sinomenine