肾间质纤维化(renal interstitial fibrosis, RIF)启动机制不明，是目前制约肾脏纤维化研究的瓶颈。肾小管上皮细胞损伤和凋亡被认为参与RIF的发生，但其触发RIF的具体信号途径至今仍缺乏清晰认识。我们前期研究发现内质网应激效应分子CHOP介导肾小管上皮细胞凋亡可能是RIF的始动因素，在RIF的动物模型中伴随HMGB1的核浆迁移和胞外释放。因此我们推测损伤导致内质网应激效应分子CHOP 驱动“损伤相关分子模式”分子HMGB1迅速从胞核迁移到胞浆胞外，诱导“瀑布般”级联炎症反应，释放促纤因子，是RIF启动的核心环节。本项目拟通过CHOP-/-小鼠、CHOP SiRNA和抗HMGB1中和抗体等，研究HMGB1核浆迁移及其调控蛋白PPARγ的变化，探讨CHOP通过PPARγ驱动肾小管上皮细胞HMGB1核浆迁移，启动RIF的假说，为RIF的防治提供新的理论依据和治疗靶点。

The initiation of renal interstitial fibrosis is strongly associated with renal tubular epithelial cells injury and apoptosis. However, the knowledge of involved mechanism and signal pathway is still limited. Our previous studies showed that endoplasmic reticulum stress effector molecule CHOP (C/EBP homologous protein) promotes renal interstitial fibrosis via up-regulating apoptosis and the secretion of proinflammatory and profibrotic factors in renal tubular epithelial cells, while we also observed the nuclear-cytoplasmic translocation and extracellular release of DAMP (Damage-Associated Molecular Pattern) molecule HMGB1 in renal interstitial fibrosis animal model. Therefore, we hypothesized that the crucial mechanism initiating renal interstitial fibrosis is: renal tubular epithelial cells injury leads to endoplasmic reticulum stress, followed by its effector molecule CHOP inciting the nuclear protein HMGB1 nuclear-cytoplasmic translocation and extracellular release, and then extracellular HMGB1 induces cascade inflammation to enhance renal interstitial fibrosis. To test this hypothesis, we will use CHOP knockout(-/-) mice, CHOP small interfering RNA and anti-HMGB1 neutralizing antibody in unilateral ureteral obstruction (UUO) model and TGF-β1 stimulated cells, to investigate the nuclear-cytoplasmic translocation of HMGB1 and the expression of its regulatory protein PPARγ in renal tubular epithelial cells , and identify that the initiation of renal fibrosis is mediated by CHOP via PPARγ regulating nuclear-cytoplasmic translocation of HMGB1, and finally provide a potential therapeutic strategy for chronic renal fibrosis.