Transcription Factor Egr1 is Involved in High Glucose-Induced Proliferation and Fibrosis in Rat Glomerular Mesangial Cells
Transcription Factor Egr1 is Involved in High Glucose-Induced Proliferation and Fibrosis in Rat Glomerular Mesangial Cells
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转录因子 Egr1 参与高糖诱导的大鼠肾小球系膜细胞增殖和纤维化
DOI：
10.1159/000430177
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发表时间：
2015-08-01
影响因子：
--
通讯作者：
Xue, Yao-Ming
中科院分区：
文献类型：
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作者：
Wang, Dan;Guan, Mei-Ping;Xue, Yao-Ming
背景：糖尿病肾病是终末期肾病的最常见原因之一，与肾小球系膜细胞（MC）增殖和细胞外基质（ECM）过度产生有关。多项研究表明，早期生长反应因子 1 (Egr1) 通过调节 ECM 成分编码基因的表达，在肾纤维化中发挥关键作用。然而，Egr1 是否也会导致糖尿病肾病尚不清楚。方法：在本研究中，我们比较了患有自发性 2 型糖尿病的 OLETF 大鼠和健康 LETO 大鼠肾脏中 Egr1 的表达。我们还检查了高葡萄糖和 TGF-β1 信号传导是否上调培养的 MC 中的 Egr1 表达，以及 Egr1 表达是否影响 MC 增殖和 ECM 基因的表达。结果：我们发现 OLETF 大鼠的肾脏与 LETO 大鼠的肾脏相比，Egr1 和 TGF-β1 在 mRNA 和蛋白质水平上的表达更高。高葡萄糖或 TGF-β1 信号传导快速上调培养的 MC 中 Egr1 mRNA 和蛋白质的表达。通过转染M61-Egr1质粒或高糖处理使MCs过度表达Egr1，上调纤连蛋白、IV型胶原和TGF-β1的表达，并促进MC增殖。相反，siRNA 介导的 Egr1 表达沉默会下调这些基因并抑制 MC 增殖。染色质免疫沉淀 (ChIP) 检测显示 Egr1 与 TGF-β1 启动子结合。结论：我们的结果提供了强有力的证据，证明 Egr1 通过增强 MC 增殖和 ECM 产生（部分是通过与 TGF-β1 相互作用）来促进糖尿病肾病。
Backgroud: Diabetic nephropathy is one of the most frequent causes of end-stage renal disease and is associated with proliferation of glomerular mesangial cells (MCs) and excessive production of the extracellular matrix (ECM). Several studies have shown that early growth response factor 1 (Egr1) plays a key role in renal fibrosis by regulating the expression of genes encoding ECM components. However, whether Egr1 also contributes to diabetic nephropathy is unclear. Methods: In the present study, we compared the expression of Egr1 in kidneys from OLETF rats with spontaneous type 2 diabetes and healthy LETO rats. We also examined whether high glucose and TGF-β1 signaling up-regulated Egr1 expression in cultured MCs, and whether Egr1 expression influenced MC proliferation and expression of ECM genes. Results: We found that higher expression of Egr1 and TGF-β1, at both the mRNA and protein levels, the kidneys from OLETF rats vs. LETO rats. High glucose or TGF-β1 signaling rapidly up-regulated expression of Egr1 mRNA and protein in cultured MCs. Overexpressing Egr1 in MCs by transfection with M61-Egr1 plasmid or treatment with high glucose up-regulated expression of fibronectin, type IV collagen and TGF-β1, and promoted MC proliferation. Conversely, siRNA-mediated silencing of Egr1 expression down-regulated these genes and inhibited MC proliferation. Chromatin immunoprecipitation (ChIP) assays revealed that Egr1 bound to the TGF-β1 promoter. Conclusion: Our results provide strong evidence that Egr1 contributes to diabetic nephropathy by enhancing MC proliferation and ECM production, in part by interacting with TGF-β1.