C3a/LINC00924通路在局灶节段肾小球硬化症肾小管间质纤维化中的作用研究

Focal segmental glomerulosclerosis (FSGS) accounts for 40% of cases of nephrotic syndrome in adults. The renal prognosis of patients with FSGS is poor, and tubulointerstitial fibrosis is one of the independent risk factors for end-stage renal disease in patients with FSGS. Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides that are not translated into protein. We recently complete a transcriptome analysis of tubulointerstitial tissues in 20 patients with FSGS and 20 normal control subjects. The level of LINC00924 is increased in renal tubular cells and shows the most significant relationship with the tubulointerstitial fibrosis score in patients with FSGS. Our pre-experiments show that the upexpression of LINC00924 in renal tubular cells may be related to the C3a/p38/XBP-1 pathway, and LINC00924 may promote the expression of snail and induce fibrogenesis through competitive binding of miR-27b in tubular cells of patients with FSGS. In the present study, experiments will be conducted both in vitro and in vivo, to investigate the clinical significance of LINC00924 expression in renal tubular cells, elucidate the reason of high expression of LINC00924, and clarify the mechanism of tubulointerstitial fibrosis induced by LINC00924 overexpression in patients with FSGS. The implementation of this project will deepen our understanding of the pathogenesis of tubulointerstitial fibrosis in patients with FSGS, and provide new targets and new methods for the protection of renal function in patients with FSGS.

局灶节段肾小球硬化症(Focal segmental glomerulosclerosis, FSGS)预后较差，肾小管间质纤维化是患者发生终末期肾病的独立风险因素。我们完成了20例FSGS和20例正常对照肾小管转录组学分析，发现长链非编码RNA LINC00924在FSGS患者肾小管上皮细胞表达增高，且与患者肾小管间质纤维化评分相关。预实验显示，FSGS患者肾小管LINC00924表达增高可能与C3a/p38/XBP-1通路有关，而LINC00924可能通过竞争性结合miR-27b，促进snail表达，诱导肾小管上皮细胞纤维化。本课题将通过临床病例、体外细胞和模型小鼠实验，分析FSGS患者肾小管LINC00924高表达的临床意义，明确FSGS患者肾小管LINC00924高表达的原因，并阐明LINC00924高表达导致FSGS患者肾小管间质纤维化的机制。本课题的实施将加深我们对FSGS肾小管间质纤维化发生机制的认识，为FSGS患者肾功能保护提供新靶点和新方法。

局灶节段肾小球硬化症（FSGS）患者多为非选择性蛋白尿，起病时高血压和肾功能损害较多见，常伴有肾小管功能的损伤。在病理上，FSGS患者表现为足细胞损伤和肾小管间质性病变。本项目通过FSGS患者肾小管间质和肾小球组织的转录组学分析以及细胞和动物实验，发现：1、FSGS患者肾小管上皮细胞LINC00924高表达，通过竞争性结合miR-93促进PDGF-BB的分泌，再激活成纤维细胞，促进FSGS患者间质纤维化。2、FSGS患者肾小管上皮细胞LOC105375913高表达，通过竞争性结合miR-27b，增加snail表达，促进肾小管上皮细胞胶原合成。3、C3a和suPAR分别通过促进转录和剪接来驱动肾小管上皮细胞versican V1的表达，肾小管上皮细胞来源的versican V1激活成纤维细胞，促进FSGS患者间质纤维化。4、LRRC55表达上调和TRPC6介导的钙离子内流，导致足细胞BK通道开放和细胞内钾离子丢失，促进凋亡小体形成和Caspase-3活化，诱导FSGS患者足细胞凋亡。本项目揭示了FSGS患者肾小管间质纤维化和足细胞损伤的新机制，为肾小管间质纤维化和足细胞损伤后干预提供了新靶点。