Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Cells Tissues Organs. 2012;195(4):296-312. doi: 10.1159/000327530. Epub 2011 Jul 19.
Mature tubular epithelial cells in the adult kidney can undergo epithelial-mesenchymal transition (EMT), a phenotypic change that is linked to the pathogenesis of renal interstitial fibrosis. EMT may be considered the reverse of mesenchymal-epithelial transition, which occurs during normal kidney development. The Wilms' tumor suppressor gene WT1 and the paired box 2 gene Pax2 are needed to induce mesenchymal-epithelial transition and play key roles in the progression of nephrogenesis. However, until now, WT1 and Pax2 have not been tested for their direct involvement in the process of renal tubular EMT. In this study, we explored the potential roles of WT1 and Pax2 in EMT that is induced in the remnant kidney of rats following 5/6 nephrectomy. We also examined WT1 and Pax2 in cultured renal tubular epithelial (NRK52E) cells treated with interleukin-1α and investigated the effects of blocking EMT using RNA interference. We showed that WT1 and Pax2 were re-expressed in the EMT models, and these were accompanied by decreased expression of E-cadherin and increased expression of vimentin, Snail and α-smooth muscle actin. Silencing WT1 and Pax2 by RNA interference blocked the interleukin-1α-induced EMT in the NRK52E cells, as reflected in the suppression of α-SMA and Snail expression, the restoration of E-cadherin expression and normal cell morphology. Our experiments suggested that the re-expression of WT1 and Pax2 in the tubular epithelial cells plays important roles in the promotion of EMT, and there may be therapeutic value in silencing Pax2 and WT1 to prevent or reverse renal fibrosis.
成人肾脏中的成熟管状上皮细胞可经历上皮-间充质转化（EMT），这是一种表型变化，与肾间质纤维化的发病机制有关。EMT 可以被认为是间充质-上皮转化的逆转，间充质-上皮转化发生在正常肾脏发育过程中。Wilms 肿瘤抑制基因 WT1 和配对盒基因 2（Pax2）对于诱导间充质-上皮转化和在肾发生进展中发挥关键作用是必需的。然而，到目前为止，WT1 和 Pax2 尚未经过测试以直接参与肾小管 EMT 过程。在这项研究中，我们探讨了 WT1 和 Pax2 在大鼠 5/6 肾切除术后残肾中诱导的 EMT 中的潜在作用。我们还研究了 WT1 和 Pax2 在培养的肾小管上皮（NRK52E）细胞中经白细胞介素-1α处理后的表达情况，并使用 RNA 干扰法研究了阻断 EMT 的效果。结果表明，在 EMT 模型中重新表达了 WT1 和 Pax2，同时 E-钙黏蛋白的表达降低，波形蛋白、Snail 和 α-平滑肌肌动蛋白的表达增加。通过 RNA 干扰沉默 WT1 和 Pax2 可阻断白细胞介素-1α诱导的 NRK52E 细胞 EMT，表现在α-SMA 和 Snail 表达受到抑制、E-钙黏蛋白表达恢复正常和细胞形态正常。我们的实验表明，WT1 和 Pax2 在肾小管上皮细胞中的重新表达在促进 EMT 中发挥重要作用，沉默 Pax2 和 WT1 可能具有预防或逆转肾纤维化的治疗价值。
