SRF调控lincRNA-p21通过miR-1184-COL1A1通路促进腹膜纤维化

腹膜纤维化导致的超滤衰竭是腹膜透析失败的原因之一，而高糖导致的人腹膜间皮细胞（HPMC）损伤是纤维化的起始阶段，可逆转纤维化过程。实验组前期证实血清反应因子（SRF）是促进高糖诱导的HPMC损伤的重要分子，但其具体调控机制不清楚。LncRNA芯片筛选及预测发现，lincRNA-p21在高糖损伤的HPMC中显著增加，可能被SRF直接调控，CLIP-seq、miRNA芯片筛选及靶分子预测结果提示：lincRNA-p21可能通过海绵效应抑制miRNA-1184，进而上调靶分子胶原蛋白Ⅰ（COL1A1），最终导致胶原纤维过度沉积及腹膜纤维化。本研究在前期基础上，在体内外水平进一步探讨高糖损伤的HPMC中SRF调控的lincRNA-p21促纤维化机制以及其下游可能的miR-1184-COL1A1分子调控通路，进而从转录因子-lncRNA-microRNA-基因的调节水平探讨腹膜纤维化的分子机制。

Previous work revealed that serum response factor (SRF) was involved in the phenotypic transition and fibrosis of the peritoneal membrane during treatment with peritoneal dialysis (PD). RNA-CHiP and lncRNA array analysis showed that, LincRNA-P21, which has a CArG element in the promoter, was found to be regulated by SRF by, but its role in peritoneal fibrosis remained unclear. Here, we found that, lincRNA-P21, which was found to be highly expressed in HG-induced HPMCs, was directly regulated by active SRF after HG stimulation in human peritoneal mesothelial cells (HPMCs) and that it contributed to peritoneal fibrosis. The silencing of lincRNA-P21 could inhibit HG-induced damage and alleviate fibrosis in PD rats in vivo, and caused cells migrated, and adhere closely in vitro. Mechanistically, lincRNA-P21 could inhibit the expression of miRNA-1184, which was characterized to target the COL1A1 messenger RNAs, and finally contribute to the adhesion of cellsin HG induced HPMCs. Overall, this study reveals a novel SRF-lincRNA-P21-miR-1184-COL1A1 axis that mediates damage and fibrosis in PD.