KIM-1介导小管上皮细胞外泌体吞噬在肾小管间质炎症中的作用及机制研究

小管上皮细胞损伤及间质炎症反应是多种急慢性肾脏损伤共同的病理改变，是决定肾脏病进展及预后的关键。然而，受损小管上皮细胞之间是否存在炎症信号的传递和具体调节机制，目前仍不清楚。我们既往研究发现，小管上皮细胞缺氧损伤时，分泌外泌体显著增加，并携带致炎因子传递到巨噬细胞，参与小管间质炎症的发生。近年的研究发现，上皮细胞KIM-1可通过特异性结合凋亡细胞表面磷脂酰丝氨酸（PS），参与炎症调节。我们最近发现，敲降KIM-1可显著抑制外泌体诱导的小管上皮细胞炎症反应。由于外泌体表面携带PS组分，我们有理由推测，小管上皮细胞KIM-1通过识别外泌体表面PS促进其摄取，从而介导小管上皮细胞之间致炎信号的传递，进一步扩大小管间质的炎症反应。本项目拟通过系统的在体模式动物、细胞培养，阐明外泌体/KIM-1介导的损伤信号传递参与小管间质炎症反应的新机制，为基于外泌体的肾脏疾病治疗提出新的靶点和实验基础。

Tubular epithelial cell (TEC) injury and tubulointerstitial inflammation are the key pathological characteristics of many types of acute and chronic kidney disease which determine the prognosis of the disease. However, the mechanisms by which the injured signals were transferred between TECs remained largely unclear. In our previous studies, we found that under hypoxia or proteinuria conditions, TECs increased exosome secretion and spread proinflammatory signals to macrophages which consequently drive interstitial inflammation. Recent studies showed that KIM-1 was upregulated in injured TECs and may participate in the process of renal inflammation. Interestingly, KIM-1 was a phosphatidylserine (PS) receptor that was responsible for phagocytosis of apoptotic cells through recognizing PS. Recently, we found that the inflammation in exosome-treated TECs was significantly reduced by knock down of KIM-1 expression. Since PS was present on outer surface of exosomes, we propose that the increased releasing of exosomes might be internalized by TECs via KIM-1 as a paracrine/autocrine signal to augment the inflammation. In this study, we plan to test this hypothesis through animal model and cell culture, the aim is to clarify a novel mechanism that KIM-1/exosomes mediated tubulointerstitial inflammation which may provide new therapeutic target for kidney disease.