miRNA-34c调控VE-cadherin表达促进肾纤维化及其机制研究

Peritubular capillary rarefaction is correlated with the severity of renal fibrosis. VE-cadherin is essential for vascular remodeling and the maintenance of vascular integrity, and suppresses renal fibrosis.Expression of miRNA-34c was markedly up-regulated,whereasexpression ofvascular endothelial cadherin (VE-cadherin) was down-regulatedinMunich WistarFromter(MWF)with inborn nephropathy in ourpreliminary test.However,it was unclear whether miRNA-34c promoted renal fibrosis by regulating expression of VE-cadherin.Previous studies reported that Klf4 positively modulates VE-cadherin and maintain vascular integrity. Result of preliminary test showed that Klf4mRNA was one of predicted target genes of miRNA-34c using TargetScan and microRNA.org. Thus, we hypothesized that miRNA-34c down-regulated expression of Klf4 by suppressing translation of Klf4mRNA, which down-regulated expression of VE-cadherin. Hence, in the present study, we willvalidate the hypothesis via the following experiments: Firstly,we will ⑴evaluate associationmiRNA-34cwith renal fibrosis in vivo;⑵validate that Klf4mRNA was one of predicted target genes of miRNA-34c by cell transfection, micro array gene chip and real-time PCR in vitro;⑶perform the vitro experiment to investigate whether miRNA-34c regulated expression of VE-cadherin by modulating expression of Klf4.⑷perform the vivo experimentto validate that miRNA-34c promoted renal fibrosis by modulating expression of VE-cadherin.The data will provide the new insight for the discovery of target genes for clinical application in renal fibrosis.

肾小管周毛细血管稀疏与肾纤维化密切相关。VE-cadherin是毛细血管重构及维持其完整性的必要因子，可抑制肾纤维化。预实验发现，先天性肾病MWF大鼠肾组织miRNA-34c表达上调，VE-cadherin表达下调。miRNA-34c是否下调VE-cadherin促进肾纤维化？目前仍不清楚。研究表明，KLF4正调控VE-cadherin表达；而Klf4mRNA是miRNA-34c预测靶基因之一。因此，miRNA-34c是否通过抑制Klf4mRNA翻译，下调Klf4表达，继而下调VE-cadherin表达促进肾纤维化？本项目：⑴体内研究miRNA-34c与肾纤维化相关性；⑵细胞水平研究Klf4mRNA是miRNA-34c的靶基因；⑶细胞水平研究miRNA-34c调控VE-cadherin表达机制；⑷体内研究验证miRNA-34c调控VE-cadherin表达促进肾纤维化。

肾小管周毛细血管稀疏与肾纤维化密切相关。VE-cadherin是毛细血管重构及维持其完整性的必要因子，可抑制肾纤维化。预实验发现，先天性肾病MWF大鼠肾组织miRNA-34c表达上调，VE-cadherin表达下调。miRNA-34c是否下调VE-cadherin促进肾纤维化？目前仍不清楚。研究表明，KLF4正调控VE-cadherin表达；而Klf4mRNA是miRNA-34c预测靶基因之一。因此，miRNA-34c是否通过抑制Klf4mRNA翻译，下调Klf4表达，继而下调VE-cadherin表达促进肾纤维化？本项目发现：⑴体内研究miRNA-34c与肾纤维化正相关；⑵细胞水平研究Klf 4mRNA是miRNA-34c的靶基因；⑶细胞水平研究miRNA-34c调控VE-cadherin表达机制；⑷体内研究验证miRNA-34c调控VE-cadherin表达促进肾纤维化。总之，miRNA-34c通过下调VE-cadherin表达促进肾纤维化。