Nrf2在EGCG改善抗GBM肾小球肾炎中的作用机制研究

Anti-GBM glomerulonephritis is pathologically and clinically the most severe form of immune-mediated glomerulonephritis. The traditional treatments, including high-dose corticosteroids, cytotoxic drugs and plasmapheresis, have the risks of infection for immunosuppression. Therefore, safer and more effective alternatives are urgently needed. The green tea catechins, particularly (-)-epigallocatechin-3-gallate (EGCG), are potent anti-inflammatory, anti-oxidant and anti-apoptosis agents. Our former study first showed EGCG could ameliorate clinic presentation and histopathologic changes of anti-GBM glomerulonephritis. This was coupled with an increasing expression of Nrf2 in the nucleus of kidney. Nrf2 is the recently found transcription nuclear factor which play a central part in the oxidative stress. It can activate antioxidant enzymes and phase 2 detoxifying enzymes and is critical for maintaining redox balance. Nrf2 can regulate apoptosis gene family and inhibit apoptosis.It also can play a role in immune regulation.This project aims to study the role of EGCG on the expression of antioxidant enzymes and phase 2 detoxifying enzymes, cell apoptosis of kidney and immune regulation through activating Nrf2. It will provide theoretic evidence for EGCG ameliorating anti-GBM glomerulonephritis and make preparation for the further study of the role of EGCG on anti-GBM glomerulonephritis.

抗GBM肾炎是临床表现及病理改变最为严重的免疫相关性肾炎，大剂量激素及免疫抑制剂等传统治疗存在全身免疫抑制而致的机会感染。寻找安全有效的治疗方法尤为重要。EGCG是绿茶多酚的主要组成部分，具有抗炎抗氧化抗凋亡作用，我们以往研究首次证实EGCG能改善抗GBM肾炎的临床表现及病理变化，上调抗GBM肾炎肾脏组织细胞核内Nrf2表达。Nrf2是新近发现的在氧化应激中起核心作用的转录激活因子，能激活参与机体抗氧化的主要抗氧化酶和II相解毒酶，对于维持机体氧化还原平衡，应对氧化应激有着关键性作用。Nrf2还能作用于细胞凋亡基因家族，抑制细胞凋亡；参与自身免疫监督调控。本项目拟探讨EGCG激活Nrf2在抗GBM肾炎中对抗氧化酶和II相解毒酶表达、肾脏组织细胞凋亡及自身免疫调控的作用，为EGCG改善抗GBM肾炎提供理论依据，并为今后全面深入探讨EGCG在抗GBM肾炎中的作用做好铺垫。

抗GBM肾炎是临床表现及病理改变最为严重的免疫相关性肾炎，氧化应激与炎症反应和细胞凋亡构成一个调控网络，在其发生发展中起到重要作用。我们前期研究证实EGCG能改善抗GBM肾炎的临床表现及病理变化，上调抗GBM肾炎肾脏组织细胞核内Nrf2表达。Nrf2是新近发现的在氧化应激中起核心作用的转录激活因子，能激活参与机体抗氧化的主要抗氧化酶和II相解毒酶，对于维持机体氧化还原平衡，应对氧化应激有着关键性作用。我们在前期研究基础上发现：1）再次论证了EGCG在抗GBM肾炎中能改善肾脏组织病理学、蛋白尿以及血肌酐；Nrf2表达异常可能参与抗GBM肾炎的发生；2）EGCG可以抑制抗GBM肾炎肾脏组织中Nrf2上游p-Akt、p-P38、p-JNK、p-ERK蛋白表达；3）EGCG可上调抗GBM肾炎肾脏组织中Nrf2下游GCLC、GCLM、GPx1蛋白表达，上调NQO1蛋白表达，对HO-1蛋白表达无影响；4）EGCG能下调抗GBM肾炎CD4+%、Th1%、Th1/Th2，降低外周血INF-γ、IL-4、IL-10水平。为EGCG改善抗GBM肾炎提供进一步理论依据，并为今后深入探讨EGCG在抗GBM肾炎中作用及寻找治疗抗GBM肾炎靶位点做好铺垫。