E-cadherin expression is regulated by miR-192/215 by a mechanism that is independent of the profibrotic effects of transforming growth factor-beta.
E-cadherin expression is regulated by miR-192/215 by a mechanism that is independent of the profibrotic effects of transforming growth factor-beta.
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DOI：
10.2337/db09-1736
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发表时间：
2010-07
期刊：
影响因子：
7.7
通讯作者：
Kantharidis P
中科院分区：
文献类型：
--
作者：
Wang B;Herman-Edelstein M;Koh P;Burns W;Jandeleit-Dahm K;Watson A;Saleem M;Goodall GJ;Twigg SM;Cooper ME;Kantharidis P
肾脏内细胞外基质 (ECM) 沉积的增加是由促纤维化介质驱动的，包括转化生长因子-β (TGF-β) 和结缔组织生长因子 (CTGF)。我们研究了它们的一些作用是否可能是通过某些 microRNA (miRNA) 表达的变化来介导的。分析近端肾小管细胞、原代大鼠系膜细胞和人足细胞暴露于 TGF-β（1-10 ng/μl）后关键基因、ECM 蛋白和 miRNA 表达的变化。管状细胞也被 CTGF-腺病毒感染。还分析了糖尿病 apoE 小鼠肾脏的基因表达和 miRNA 水平的变化。 TGF-β治疗与上皮间质转化（EMT）典型的形态和表型变化相关，包括所有肾细胞类型的纤维形成增加和肾小管细胞中E-钙粘蛋白表达减少。 TGF-β治疗还调节某些miRNA的表达，包括肾小管细胞、系膜细胞中miR-192/215的表达降低，糖尿病肾脏中的miR-192/215表达也降低。在存在或不存在 TGF-β 的情况下，miR-192/215 的异位表达通过抑制 ZEB2 mRNA 的翻译增加 E-钙粘蛋白水平，如 ZEB2 3'-非翻译区荧光素酶报告基因测定所证明。然而，miR-192/215的异位表达并不影响基质蛋白的表达或TGF-β对其的诱导。相反，CTGF 增加 miR-192/215 水平，导致 ZEB2 减少，从而增加 E-钙粘蛋白 mRNA。这些数据证明了 miRNA-192/215 和 ZEB2 在 TGF-β/CTGF 介导的 E-钙粘蛋白表达变化中的关联作用。这些变化的发生似乎与基质蛋白合成的增强无关，表明多步骤 EMT 程序对于纤维发生的发生来说并不是必需的。
Increased deposition of extracellular matrix (ECM) within the kidney is driven by profibrotic mediators including transforming growth factor-β (TGF-β) and connective tissue growth factor (CTGF). We investigated whether some of their effects may be mediated through changes in expression of certain microRNAs (miRNAs). Proximal tubular cells, primary rat mesangial cells, and human podocytes were analyzed for changes in the expression of key genes, ECM proteins, and miRNA after exposure to TGF-β (1–10 ng/μl). Tubular cells were also infected with CTGF-adenovirus. Kidneys from diabetic apoE mice were also analyzed for changes in gene expression and miRNA levels. TGF-β treatment was associated with morphologic and phenotypic changes typical of epithelial-mesenchymal transition (EMT) including increased fibrogenesis in all renal cell types and decreased E-cadherin expression in tubular cells. TGF-β treatment also modulated the expression of certain miRNAs, including decreased expression of miR-192/215 in tubular cells, mesangial cells, which are also decreased in diabetic kidney. Ectopic expression of miR-192/215 increased E-cadherin levels via repressed translation of ZEB2 mRNA, in the presence and absence of TGF-β, as demonstrated by a ZEB2 3′-untranslated region luciferase reporter assay. However, ectopic expression of miR-192/215 did not affect the expression of matrix proteins or their induction by TGF-β. In contrast, CTGF increased miR-192/215 levels, causing a decrease in ZEB2, and consequently increased E-cadherin mRNA. These data demonstrate the linking role of miRNA-192/215 and ZEB2 in TGF-β/CTGF–mediated changes in E-cadherin expression. These changes appear to occur independently of augmentation of matrix protein synthesis, suggesting that a multistep EMT program is not necessary for fibrogenesis to occur.
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