缺氧是肾间质纤维化（RIF）的始动因素。文献及我们前期研究表明，人附睾蛋白4（HE4）在RIF过程中发挥重要作用，但机制尚未阐明。外泌体可参与多种生物学过程。我们发现，缺氧可上调肾小管上皮细胞内HE4和p53表达，并促使其释放携带HE4的外泌体。文献报道，p53可调控多种细胞胞吐。进一步生物信息学分析发现，p53和HE4启动子区均存在HIF-1α结合位点。同时证实，携带HE4的外泌体可刺激成纤维细胞增殖活化并激活NF-κB通路。本课题拟在此基础上，深入研究缺氧诱导肾小管上皮细胞释放携带HE4的外泌体在RIF中的作用；揭示HIF-1α、p53和HE4之间的关系在缺氧诱导肾小管上皮细胞释放携带HE4的外泌体中的意义；阐明NF-κB通路在携带HE4的外泌体调控RIF中的作用和机制。这些研究可以明确缺氧通过调控肾小管上皮细胞释放携带HE4的外泌体参与RIF的分子机制，具有重要理论意义。

Hypoxia is an important initial factor of renal interstitial fibrosis (RIF). Previous studies and our results demonstrated that human epididymis protein-4 (HE4) plays an important role in RIF. However, the molecular mechanism of HE4 for RIF has not been well elucidated. Exosome participates in many biological processes. We found that hypoxia upregulated the expression of p53 and HE4 and induced renal epithelial cells to release HE4 exosomes. Several studies proved that p53 can medicate exocytosis. And, our bioinformatics analysis showed that HIF-1α could bind to the 3‘UTR of p53 and HE4. And, in vitro experiments suggested that the HE4 exosome can promote the activation and proliferation of fibroblasts and activated the NF-κB pathway. Therefore, the purposes of our present study are following: i) to confirm the role of HE4 exosome from renal epithelial cells on the hypoxia induced RIF, ii) to figure out whether hypoxia induces renal epithelial cells to release HE4 exosomes through the HIF-1α/p53 and HIF-1α/HE4 pathways, and iii) to clarify if the HE4 exosome promotes RIF through the NF-κB pathway. Our present study will clarify the molecular pathways of the hypoxia-induced HE4 exosome release and the HE4 exosome induced RIF. Most likely, these results will be associated with important theoretical significance.