Erythropoietin decreases renal fibrosis in mice with ureteral obstruction:: Role of inhibiting TGF-β-induced epithelial-to-mesenchymal transition
Erythropoietin decreases renal fibrosis in mice with ureteral obstruction:: Role of inhibiting TGF-β-induced epithelial-to-mesenchymal transition
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DOI：
10.1681/asn.2005080866
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发表时间：
2007-05-01
影响因子：
13.6
通讯作者：
Kim, Yong-Lim
中科院分区：
文献类型：
--
作者：
Park, Sun-Hee;Choi, Min-Jeong;Kim, Yong-Lim
研究了重组人促红细胞生成素（rhEPO）对（1）单侧输尿管完全梗阻小鼠肾纤维化进展和（2）TGF-β 1诱导的MDCK细胞上皮间质转化（EMT）的抑制作用。在BALB/c小鼠中诱导单侧输尿管梗阻，并从第3天至第14天给予rhEPO（100或1000 U/kg，腹膜内，每隔一天）或载体。免疫印迹和免疫组化显示，TGF-β 1，α-平滑肌肌动蛋白（α-SMA），纤维连接蛋白和表达增加，E-钙粘蛋白的表达减少，在梗阻的肾脏。与此相反，rhEPO治疗显著减弱了TGF-β 1和α-SMA的上调以及E-钙粘蛋白的下调。用TGF-β 1（5 ng/ml）处理MDCK细胞48 h诱导EMT，然后用TGF-β 1和rhEPO共同处理48 h。TGF-β 1处理后，观察到α-SMA和波形蛋白表达增加，而E-cadherin和E-cadherin表达减少，rhEPO共同处理后这些变化明显减弱。TGF-β 1增加MDCK细胞中磷酸化Smad-2的表达，而rhEPO联合处理则降低其表达。总之，rhEPO治疗抑制阻塞肾中肾纤维化的进展，并减弱TGF-β 1诱导的EMT。这表明，rhEPO的肾脏保护作用可以介导，至少部分，通过抑制TGF-β 1诱导的EMT。
The inhibitory effects of recombinant human erythropoietin (rhEPO) were examined against (1) the progression of renal fibrosis in mice with complete unilateral ureteral obstruction and (2) the TGF-beta 1-induced epithelial-to-mesenchymal transition (EMT) in MDCK cells. Unilateral ureteral obstruction was induced in BALB/c mice and rhEPO (100 or 1000 U/kg, intraperitoneally, every other day) or vehicle was administered from day 3 to day 14. Immunoblotting and immunohistochemistry revealed increased expressions of TGF-beta 1, alpha-smooth muscle actin (alpha-SMA), and fibronectin and decreased expression of E-cadherin in the obstructed kidneys. In contrast, rhEPO treatment significantly attenuated the upregulation of TGF-beta 1 and alpha-SMA and the downregulation of E-cadherin. MDCK cells were treated with TGF-beta 1 (5 ng/ml) for 48 h to induce EMT, and the cells were then co-treated with TGF-beta 1 and rhEPO for another 48 It. Increased expressions of a-SMA and vimentin and decreased expressions of zona occludens-1 and E-cadherin were observed after TGF-beta 1 treatment, and these changes were markedly attenuated by rhEPO co-treatment. TGF-beta 1 increased phosphorylated Smad-2 expression in MDCK cells, which was decreased by rhEPO co-treatment. In conclusion, rhEPO treatment inhibits the progression of renal fibrosis in obstructed kidney and attenuates the TGF-beta 1-induced EMT. It is suggested that the renoprotective effects of rhEPO could be mediated, at least partly, by inhibition of TGF-beta 1-induced EMT.