肾间质纤维化的启动机制是亟待攻克的科学难题。毛细血管稀疏诱导的缺氧微环境是启动和促进间质纤维化的关键，我们前期研究发现缺血再灌注损伤(IRI)诱导的肾间质纤维化模型中管周毛细血管稀疏、周细胞-内皮细胞脱离，而该过程伴随细胞间隙连接蛋白Cx43的表达显著上调，推测Cx43介导周细胞-内皮细胞的脱离可能参与了肾间质纤维化的发生发展。因此，我们假设缺氧早期毛细血管内皮细胞受损，细胞间的Cx43通道增加并传递促凋亡、坏死信号，内皮细胞大量凋亡坏死，导致周细胞与内皮细胞脱离，继而周细胞增殖并向肌成纤维细胞转分化。本项目将建立IRI和UUO诱导的肾间质纤维化模型，采用选择性内皮细胞和周细胞Cx43基因敲除小鼠以及Cx43模拟多肽等，探讨Cx43参与毛细血管稀疏、周细胞增殖和转分化的具体机制，证实Cx43通过介导周细胞-内皮细胞脱离而调控肾间质纤维化的假说，为临床肾间质纤维化的早期干预提供新策略。

The mechanism on initiation of renal interstitial fibrosis (RIF) remains largely elusive as of today. We believe that microvascular rarefarction-induced local hypoxia plays a key role in the initiation and progression of RIF. In our previous ischemia-reperfusion injury (IRI) study, we observed that peritubular capillary rarefarction and the detachment of pericytes from endothelial cells, accompanied by the overexpression of gap junction protein connexin 43 (Cx43). We hypothesized in the early stage of hypoxia, capillary endothelial cells injury amplified the pro-apoptosis and necrosis factor signals via Cx43 channel located in the endothelia cells, causing the detachment of pericytes from endothelial cells, and pericytes proliferation and pericyte-myofibroblast transition. In the IRI and UUO induced RIF animal models, we will use Cx43 mimetic peptide and endothelial cell-specific and pericyte-specific Cx43 knockout mice to investigate the mechanism of Cx43 involved in the regulation of capillary rarefaction, pericytes proliferation and transition, and to confirm the hypothesis that Cx43 regulates the RIF by mediating the detachment of pericytes from endothelial cells. Our goal is to elucidate the pathophysiology of the RIF and to provide a new therapeutic insight for RIF.