Epigallocatechin gallate upregulates NRF2 to prevent diabetic nephropathy via disabling KEAP1
Epigallocatechin gallate upregulates NRF2 to prevent diabetic nephropathy via disabling KEAP1
复制标题
表没食子儿茶素没食子酸酯上调 NRF2，通过禁用 KEAP1 来预防糖尿病肾病
DOI：
10.1016/j.freeradbiomed.2017.04.365
复制
发表时间：
2017-07-01
影响因子：
7.4
通讯作者：
Wu, Hao
中科院分区：
文献类型：
--
作者：
Sun, Weixia;Liu, Xiuxia;Wu, Hao
表没食子儿茶素没食子酸酯（Epigallocatechin gallate，EGCG）是绿色茶中含量最丰富、最有效的儿茶素，据报道可减轻糖尿病肾病（diabetic nephropathy，DN）。然而，迄今为止，EGCG改善DN的机制仍不清楚。表没食子儿茶素没食子酸酯是核因子红细胞2相关因子2（NRF 2）的有效激活剂，NRF 2在细胞防御糖尿病诱导的氧化应激和预防DN中起关键作用。在本研究中，我们测试了NRF 2是否是EGCG保护DN所必需的。因此，C57 BL/6野生型（WT）和Nrf 2敲除小鼠在存在或不存在24周的EGCG治疗的情况下通过链脲佐菌素诱导糖尿病。在WT小鼠中，EGCG激活Nrf 2的表达和功能，而不改变Kelch样ECH相关蛋白1（Keap 1）的表达。糖尿病引起的肾脏氧化损伤，炎症，纤维化和蛋白尿显着防止表没食子酸酯。值得注意的是，Nrf 2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KEAP 1/NRF 2信号传导的影响，在Keap 1 siRNA和EGCG两者存在下，用高葡萄糖处理小鼠系膜细胞。有趣的是，在Keap 1 siRNA存在下，EGCG未能增强NRF 2信号传导并减轻氧化，炎症和纤维化指标。本研究首次证明，NRF 2在EGCG保护DN中起关键作用。其他研究结果表明，KEAP 1蛋白的失活由EGCG介导的EGCG激活NRF 2的功能。
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.