Advanced glycation end-products induce connective tissue growth factor-mediated renal fibrosis predominantly through transforming growth factor beta-independent pathway.
Advanced glycation end-products induce connective tissue growth factor-mediated renal fibrosis predominantly through transforming growth factor beta-independent pathway.
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DOI：
10.1016/s0002-9440(10)63254-3
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发表时间：
2004-12
期刊：
影响因子：
--
通讯作者：
Guihua Zhou;Cai Li;L. Cai
中科院分区：
文献类型：
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作者：
Guihua Zhou;Cai Li;L. Cai
晚期糖基化终产物 (AGE) 通过刺激细胞外基质 (ECM) 合成在糖尿病肾病中发挥关键作用。结缔组织生长因子 (CTGF) 是 ECM 合成的有效诱导剂，并且在糖尿病肾脏中会增加。为了确定 CTGF 在 AGE 诱导的 ECM 积累导致糖尿病肾病中的关键作用，大鼠通过静脉注射 AGE 持续 6 周。 AGE 治疗诱导显着的肾脏 ECM 积聚，表现为肾小球中高碘酸希夫阳性物质、纤连蛋白和 IV 型胶原 (Col IV) 积聚的增加，以及轻度肾功能障碍，表现为尿量和蛋白质含量的增加。 AGE 治疗还导致肾脏 CTGF 和转化生长因子 (TGF)-β1 mRNA 和蛋白表达显着增加。体外将大鼠系膜细胞直接暴露于 AGE 会显着诱导纤连蛋白和 Col IV 产生的增加，而用抗 CTGF 抗体预处理可以完全阻止这种情况的发生。 AGE 治疗还显着增加了 TGF-β1 和 CTGF mRNA 表达；然而，shRNA抑制TGF-β1 mRNA表达或抗TGF-β1抗体中和TGF-β1蛋白并不能显着阻止AGE增加的CTGF mRNA和蛋白表达。这些结果表明，AGE 诱导的 CTGF 表达（主要通过 TGF-β1 独立途径）在导致糖尿病肾病的肾脏 ECM 积累中发挥着关键作用。
Advanced glycation end-products (AGEs) play a critical role in diabetic nephropathy by stimulating extracellular matrix (ECM) synthesis. Connective tissue growth factor (CTGF) is a potent inducer of ECM synthesis and increases in the diabetic kidneys. To determine the critical role of CTGF in AGE-induced ECM accumulation leading to diabetic nephropathy, rats were given AGEs by intravenous injection for 6 weeks. AGE treatment induced a significant renal ECM accumulation, as shown by increases in periodic acid-Schiff-positive materials, fibronectin, and type IV collagen (Col IV) accumulation in glomeruli, and a mild renal dysfunction, as shown by increases in urinary volume and protein content. AGE treatment also caused significant increases in renal CTGF and transforming growth factor (TGF)-β1 mRNA and protein expression. Direct exposure of rat mesangial cells to AGEs in vitro significantly induced increases in fibronectin and Col IV production, which could be completely prevented by pretreatment with anti-CTGF antibody. AGE treatment also significantly increased both TGF-β1 and CTGF mRNA expression; however, inhibition of TGF-β1 mRNA expression by shRNA or neutralization of TGF-β1 protein by anti-TGF-β1 antibody did not significantly prevent AGE-increased expression of CTGF mRNA and protein. These results suggest that AGE-induced CTGF expression, predominantly through a TGF-β1-independent pathway, plays a critical role in renal ECM accumulation leading to diabetic nephropathy.