IL-33/ST2调控肥大细胞自噬在肾纤维化中的作用及机制

肾脏纤维化是慢性肾脏病进展的最后归宿，明确其发生发展机制对早期预防和干预具有重要的意义。研究表明，肥大细胞在肾纤维化进程中起到重要作用，但机制尚不明确。前期我们证实，IL-33、ST2及肥大细胞在小鼠肾纤维化模型的早期表达显著升高，而加入肥大细胞稳定剂可减轻肾纤维化；进一步发现肥大细胞可被IL-33激活，同时其表达LC3-II/I增加，自噬小体增多并可促使肾小管内皮细胞VEGF-C表达上调，而后者又可促进淋巴管新生并与肾纤维化的程度密切相关。据此推测IL-33/ST2可能通过调控肥大细胞自噬促进淋巴管新生继而诱导肾纤维化。为此，本项目拟首先明确IL-33/ST2、肥大细胞在肾脏组织中的表达及其与肾纤维化的关系和临床意义；接下来观察IL-33对肥大细胞自噬与功能的影响，及其是否通过调控肥大细胞自噬促进淋巴管新生继而诱导肾纤维化；最后对其机制进行初步探讨。为肾纤维化的防治提供新的思路与手段。

Renal fibrosis is the common ending of chronic kidney disease. It is of great significance for its prevention and early intervention to make the mechanism of its occurrence and development clear. Studies have shown that mast cells play an important role in renal fibrosis, but the mechanism is not clear. We confirmed that the expression of IL-33, ST2 and mast cells were significantly increased at the early stage of renal fibrosis in mice, and mast cells stabilizers reduced renal fibrosis. Furthermore, mast cells were activated by IL-33, accompanied by increased LC3-II/I ratio and autophagosome number. Mast cells activation also promoted VEGF-C expression in renal tubular endothelial cells, which in turn promoted lymphangiogenesis and was closely related to renal fibrosis. Wu thus supposed IL-33/ST2 might promote renal fibrosis through regulating the autophagy of mast cells and followed lymphangiogenesis. To this end, first the expression and clinical significance of IL-33/ST2 and mast cells in kidney and its relationship with renal fibrosis will be explored, then the impact of IL-33 on mast cells autophagy and function will be observed, and whether IL-33 induces renal fibrosis through regulating mast cells autophagy will also be discussed. Finally the mechanism will be explored, providing new ideas to the prevention and treatment of renal fibrosis.