Sinomenine activation of Nrf2 signaling prevents hyperactive inflammation and kidney injury in a mouse model of obstructive nephropathy
Sinomenine activation of Nrf2 signaling prevents hyperactive inflammation and kidney injury in a mouse model of obstructive nephropathy
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青藤碱激活 Nrf2 信号可预防阻塞性肾病小鼠模型的过度炎症和肾损伤
DOI：
10.1016/j.freeradbiomed.2016.01.011
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发表时间：
2016-03-01
影响因子：
7.4
通讯作者：
Cao, Wangsen
中科院分区：
文献类型：
--
作者：
Qin, Tian;Du, Ronghui;Cao, Wangsen
青藤碱最初是从草药中提取的，在远东地区优先用于治疗类风湿性疾病。SIN具有很强的抗炎和免疫调节作用，主要通过抑制NF-κ B信号通路发挥作用。尽管SIN影响NF-κ B活性的上游靶点尚不清楚，但有证据表明SIN可能通过Nrf 2信号传导调节炎症。在这项研究中，我们探讨了Nrf 2在介导SIN的抗炎和肾脏保护在小鼠梗阻性肾病模型中的作用。我们发现SIN是Nrf 2信号传导的激活剂。显著增加Nrf 2蛋白水平、Nrf 2核转位、Nef 2转录能力和下游蛋白表达。我们进一步证明，SIN激活Nrf 2可能是由于其抑制Nrf 2抑制剂Keap 1，因为它通过PKC敏感的泛素化-蛋白酶体降解大幅减少Keap 1蛋白。SIN治疗肾病小鼠有效地减轻了肾脏损伤和炎症反应，平衡了肾脏氧化应激，并以Nrf 2依赖的方式改善了病理蛋白表达。此外，SIN还依赖于Nrf 2调节巨噬细胞M1/M2极化，抑制Ik B α磷酸化和NF-κ B B核转位，从而揭示了其抗炎和组织保护的重要上游事件。总之，我们的研究确定了SIN发挥其抗炎和肾脏保护功能的新途径，并为SIN在肾脏和其他炎症性疾病的治疗中的潜在应用提供了分子基础。(C)2016 Elsevier Inc. All rights reserved.
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-kappa B signaling. Although the upstream target through which SIN affects NF-kappa B 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 IkB alpha phosphorylation and NF-kappa B 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. (C) 2016 Elsevier Inc. All rights reserved.