Department and Institute of Life Science, Fu-Jen Catholic University, Taipei, Taiwan.
Diabetes Metab Res Rev. 2010 Jul;26(5):406-16. doi: 10.1002/dmrr.1100.
Diabetic nephropathy has attracted many researchers' attention. Because of the emerging evidence about the effects of advanced glycation end products (AGEs) and receptor of AGE (RAGE) on the progression of diabetic nephropathy, a number of different therapies to inhibit AGE or RAGE are under investigation. The purpose of the present study was to examine whether peroxisome proliferator-activated receptor delta (PPARdelta) agonist (L-165041) or epigallocatechin gallate (EGCG) alters AGE-induced pro-inflammatory gene expression and apoptosis in human embryonic kidney cells (HEK293) and human mesangial cells (HMCs).
The HEK cells and HMC were separated into the following groups: 100 microg/mL AGE alone for 18 h; AGE treated with 1 microM L-165041 or 10 microM EGCG, and untreated cells. Inflammatory cytokines, nuclear factor-kappaB pathway, RAGE expression, superoxide dismutase and cell apoptosis were determined.
AGE significantly increased tumour necrosis factor-alpha (TNF-alpha), a major pro-inflammatory cytokine. The mRNA and protein expression of RAGE were up-regulated. These effects were significantly attenuated by pre-treatment with L-165041 or EGCG. AGE-induced nuclear factor-kappaB pathway activation and both cells apoptosis were also inhibited by L-165041 or EGCG. Furthermore, both L-165041 and EGCG increased superoxide dismutase levels in AGE-treated HEK cells and HMC.
This study demonstrated that PPARdelta agonist and EGCG decreased the AGE-induced kidney cell inflammation and apoptosis. This study provides important insights into the molecular mechanisms of EGCG and PPARdelta agonist in attenuation of kidney cell inflammation and may serve as a therapeutic modality to treat patients with diabetic nephropathy.
糖尿病肾病引起了许多研究人员的关注。由于关于晚期糖基化终产物（AGE）和 AGE 受体（RAGE）对糖尿病肾病进展的影响的新证据不断出现，许多不同的抑制 AGE 或 RAGE 的治疗方法正在研究中。本研究的目的是研究过氧化物酶体增殖物激活受体δ（PPARδ）激动剂（L-165041）或表没食子儿茶素没食子酸酯（EGCG）是否能改变 AGE 诱导的人胚肾细胞（HEK293）和人肾小球系膜细胞（HMC）中的促炎基因表达和细胞凋亡。
将 HEK 细胞和 HMC 分为以下几组：单独用 100μg/mL AGE 处理 18 小时；用 1μM L-165041 或 10μM EGCG 处理 AGE，以及未处理的细胞。测定炎症细胞因子、核因子-κB 通路、RAGE 表达、超氧化物歧化酶和细胞凋亡。
AGE 显著增加肿瘤坏死因子-α（TNF-α），这是一种主要的促炎细胞因子。RAGE 的 mRNA 和蛋白表达上调。这些作用通过用 L-165041 或 EGCG 预处理明显减弱。AGE 诱导的核因子-κB 通路激活和两种细胞凋亡也被 L-165041 或 EGCG 抑制。此外，L-165041 和 EGCG 均增加了 AGE 处理的 HEK 细胞和 HMC 中的超氧化物歧化酶水平。
本研究表明，PPARδ 激动剂和 EGCG 降低了 AGE 诱导的肾脏细胞炎症和凋亡。本研究为 EGCG 和 PPARδ 激动剂在减轻肾脏细胞炎症中的分子机制提供了重要的见解，并可能成为治疗糖尿病肾病患者的一种治疗方法。
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