Sun Weixia, Liu Xiuxia, Zhang Haifeng, Song Yanyan, Li Tie, Liu Xiaona, Liu Yanze, Guo Le, Wang Fuchun, Yang Ting, Guo Weiying, Wu Junduo, Jin Hang, Wu Hao
Department of Nephrology, The First Hospital of Jilin University, 71 Xinmin St., Changchun, Jilin 130021, People's Republic of China.
Department of Clinical Laboratory, The Second Hospital of Jilin University, 218 Ziqiang St., Changchun, Jilin 130041, People's Republic of China.
Free Radic Biol Med. 2017 Jul;108:840-857. doi: 10.1016/j.freeradbiomed.2017.04.365. Epub 2017 Apr 27.
Epigallocatechin gallate (EGCG) is the most abundant and effective green tea catechin and has been reported to attenuate diabetic nephropathy (DN). However, the mechanism by which EGCG ameliorates DN, till now, has remained unclear. EGCG is known as a potent activator of nuclear factor erythroid 2-related factor 2 (NRF2), which plays a key role in cellular defense against diabetes-induced oxidative stress and in the prevention of DN. In the present study, we tested whether NRF2 is required for EGCG protection against DN. Therefore, C57BL/6 wild type (WT) and Nrf2 knockout mice were induced to diabetes by streptozotocin, in the presence or absence of a 24-week treatment with EGCG. In the WT mice, EGCG activated Nrf2 expression and function without altering the expression of Kelch-like ECH-associated protein 1 (Keap1). Diabetes-induced renal oxidative damage, inflammation, fibrosis and albuminuria were significantly prevented by EGCG. Notably, deletion of the Nrf2 gene completely abrogated these actions of EGCG. To further determine the effect of EGCG on KEAP1/NRF2 signaling, mouse mesangial cells were treated with high glucose, in the presence of both Keap1 siRNA and EGCG. Interestingly, EGCG failed to enhance NRF2 signaling and alleviate oxidative, inflammatory and fibrotic indicators, in the presence of Keap1 siRNA. The present study demonstrated, for the first time, that NRF2 plays a critical role in EGCG protection against DN. Other findings indicated that inactivation of KEAP1 protein by EGCG may mediate EGCG function in activating NRF2.
表没食子儿茶素没食子酸酯（EGCG）是绿茶中含量最丰富且最有效的儿茶素，据报道它可减轻糖尿病肾病（DN）。然而，迄今为止，EGCG改善DN的机制仍不清楚。EGCG是核因子红细胞2相关因子2（NRF2）的有效激活剂，NRF2在细胞抵御糖尿病诱导的氧化应激以及预防DN中起关键作用。在本研究中，我们测试了NRF2是否是EGCG保护DN所必需的。因此，将C57BL/6野生型（WT）和Nrf2基因敲除小鼠用链脲佐菌素诱导糖尿病，同时给予或不给予EGCG进行24周治疗。在WT小鼠中，EGCG激活了Nrf2的表达和功能，而未改变 Kelch样ECH相关蛋白1（Keap1）的表达。EGCG显著预防了糖尿病诱导的肾脏氧化损伤、炎症、纤维化和蛋白尿。值得注意的是，Nrf2基因的缺失完全消除了EGCG的这些作用。为了进一步确定EGCG对KEAP1/NRF2信号通路的影响，在存在Keap1 siRNA和EGCG的情况下，用高糖处理小鼠系膜细胞。有趣的是，在存在Keap1 siRNA的情况下，EGCG未能增强NRF2信号通路并减轻氧化、炎症和纤维化指标。本研究首次证明，NRF2在EGCG保护DN中起关键作用。其他研究结果表明，EGCG使KEAP1蛋白失活可能介导了EGCG激活NRF2的功能。
