Thangapandiyan S, Miltonprabu S
Department of Zoology, Annamalai University, Annamalainagar 608002, Tamilnadu, India.
Toxicol Rep. 2014 Mar 27;1:12-30. doi: 10.1016/j.toxrep.2014.01.002. eCollection 2014.
Fluoride intoxication generates free radicals, causing oxidative stress that plays a critical role in the progression of nephropathy. In the present study, we hypothesized that epigallocatechin gallate (EGCG), found in green tea, protects the kidneys of rats treated with fluoride by preventing oxidative stress, inflammation, and apoptosis. Pretreatment of fluoride-treated rats with EGCG resulted in a significant normalization of creatinine clearance and levels of urea, uric acid, and creatinine. Fluoride intoxication significantly increased renal oxidative stress markers and decreased the levels of renal enzymatic and non-enzymatic antioxidants. In addition, renal NO, TNF-α, IL-6 and NF-κB were also increased in the renal tissue of fluoride-treated rats. Further, EGCG pretreatment produced a significant improvement in renal antioxidant status and reduced lipid peroxidation, protein carbonylation and the levels of inflammatory markers in fluoride-treated kidney. Similarly, mRNA and protein analyses showed that EGCG pretreatment normalized the renal expression of Nrf2/Keap1 and its downstream regulatory proteins in fluoride-treated rat kidney. EGCG also effectively attenuated fluoride-induced renal apoptosis by the up-regulation of anti-apoptotic proteins such as Bcl-2 and down-regulation of Bax, caspase-3, caspase-9 and cytochrome c. Histology and immunohistochemical observations of Kim-1 provided further evidence that EGCG effectively protects the kidney from fluoride-mediated oxidative damage. These results suggest that EGCG ameliorates fluoride-induced oxidative renal injury by activation of the Nrf2/HO-1 pathway.
氟中毒会产生自由基，引发氧化应激，而氧化应激在肾病进展中起着关键作用。在本研究中，我们假设绿茶中含有的表没食子儿茶素没食子酸酯（EGCG）可通过预防氧化应激、炎症和细胞凋亡来保护氟处理大鼠的肾脏。用EGCG对氟处理大鼠进行预处理可使肌酐清除率以及尿素、尿酸和肌酐水平显著恢复正常。氟中毒显著增加了肾脏氧化应激标志物的水平，并降低了肾脏酶促和非酶促抗氧化剂的水平。此外，氟处理大鼠肾组织中的一氧化氮（NO）、肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和核因子-κB（NF-κB）水平也有所升高。此外，EGCG预处理显著改善了肾脏抗氧化状态，减少了脂质过氧化、蛋白质羰基化以及氟处理肾脏中炎症标志物的水平。同样，mRNA和蛋白质分析表明，EGCG预处理使氟处理大鼠肾脏中Nrf2/Keap1及其下游调节蛋白的肾脏表达恢复正常。EGCG还通过上调抗凋亡蛋白如Bcl-2以及下调Bax、半胱天冬酶-3（caspase-3）、半胱天冬酶-9（caspase-9）和细胞色素c，有效减轻了氟诱导的肾脏细胞凋亡。Kim-1的组织学和免疫组织化学观察提供了进一步证据，表明EGCG可有效保护肾脏免受氟介导的氧化损伤。这些结果表明，EGCG通过激活Nrf2/HO-1途径改善氟诱导的肾脏氧化损伤。
