Indoxyl sulfate-induced epithelial-to-mesenchymal transition and apoptosis of renal tubular cells as novel mechanisms of progression of renal disease
Indoxyl sulfate-induced epithelial-to-mesenchymal transition and apoptosis of renal tubular cells as novel mechanisms of progression of renal disease
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DOI：
10.1038/labinvest.2011.194
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发表时间：
2012-04-01
影响因子：
5
通讯作者：
Kang, Duk-Hee
中科院分区：
文献类型：
--
作者：
Kim, Su Hyun;Yu, Min-A;Kang, Duk-Hee
硫酸吲哚酚（IS）是尿毒症毒素之一，被认为在慢性肾脏病（CKD）的进展中起重要作用。上皮细胞向间质细胞转化（EMT）和肾小管细胞凋亡是CKD发生和加重的重要机制。我们研究了IS对近端肾小管上皮细胞NRK-52 E的EMT和凋亡的影响。IS显著抑制细胞增殖并诱导细胞迁移，其形态从立方上皮细胞转变为梭形散在的成纤维细胞样细胞。IS在48 h下调闭合小带-1和E-cadherin的表达，而上调α-SMA的表达，这被有机阴离子转运体丙磺舒的预处理所阻断。25 μ g/ml的IS还诱导NRK细胞凋亡，并激活ERK 1/2和p38 MAP激酶（MAPK）。ERK 1/2或p38 MAPK抑制剂PD 98059或SB 203580预处理对IS诱导的EMT无明显影响，但可改善IS诱导的NRK细胞凋亡。这些结果表明，表型转换和细胞凋亡的IS诱导的肾损害的潜在机制和MAPK激活的IS诱导的EMT和肾小管细胞凋亡的差异作用。实验室调查（2012）92，488-498; doi：10.1038/labinvest.2011.194; 2012年1月9日在线发表
Indoxyl sulfate (IS), one of the uremic toxins, is regarded to have a substantial role in the progression of chronic kidney disease (CKD). Epithelial-to-mesenchymal transition (EMT) and apoptosis of renal tubular cells are known to be the critical mechanisms of the development and aggravation of CKD. We investigated the effect of IS on EMT and apoptosis in renal proximal tubular cells, NRK-52E cells. IS significantly inhibited cell proliferation and induced cell migration with a morphological transition from cuboidal epithelial cells to spindle-shaped scattered fibroblast-like cells. IS downregulated the expressions of zonula occluden-1 and E-cadherin, whereas upregulated alpha-SMA expression at 48 h, which was blocked by a pretreatment of the organic anion transporter, probenecid. IS also induced apoptosis of NRK cells from a concentration of 25 mu g/ml with an activation of ERK1/2 and p38 MAP kinase (MAPK). Pretreatment of ERK1/2 or p38 MAPK inhibitors, PD98059 or SB203580, resulted in no significant effect on IS-induced EMT, whereas it ameliorated IS-induced apoptosis of NRK cells. These findings suggested phenotypic transition and apoptosis as potential mechanisms of IS-induced renal damage and the differential role of MAPK activation in IS-induced EMT and apoptosis of renal tubular cells. Laboratory Investigation (2012) 92, 488-498; doi:10.1038/labinvest.2011.194; published online 9 January 2012