超低分子透明质酸通过激活LYVE-1通路促进淋巴管生成调控AKI向CKD转归的机制研究

相当比例的AKI会转归到CKD,带来巨大的经济和社会负担, 因此明确该过程发生的机制具有重大意义。结合前期研究成果，本项目提出以下假设：肾脏严重损伤导致超低分子透明质酸（HA）在肾脏的大量生成，后者通过与淋巴管内皮细胞上LYVE-1受体结合促进淋巴管内皮细胞的增殖、活化，引起肾脏和肾周引流淋巴结内淋巴管的新生。活化的淋巴管内皮细胞大量表达CCL21,ICAM-1,VCAM-1等导致更多CCR7+的树突状细胞通过新生淋巴管转运至肾周引流淋巴结激活效应性淋巴细胞，后者进一步被募集至肾脏导致包括肾小管上皮细胞和管周毛细血管损伤加剧，从而促进AKI向CKD的转归。本项目拟采用PROX1+淋巴管内皮细胞上LYVE-1条件性敲除和敲入转基因小鼠，明确超低分子HA通过LYVE-1通过调控淋巴管新生，进而激活获得性免疫应答，促进AKI向CKD转归的机制，探索阻断或延缓AKI向CKD转归的新策略。

A considerable proportion of AKI will progress to CKD, which will bring huge economic and social burden, so it is of great value to clarify its pathogenesis. Combined with previous research results, this project proposes the following hypothesis: severe renal damage leads to the massive production of ultra-low molecular hyaluronic acid (HA) in the kidney, the latter promotes the proliferation and activation of lymphatic endothelial cells by binding with LYVE-1 receptor on lymphatic endothelial cells, and causes lymphangiogenesis in the kidney and its draining lymph nodes. Activated lymphatic endothelial cells expressed CCL21, ICAM-1, VCAM-1 and so on, which led to more CCR7 potisive dendritic cells being transported to the renal draining lymph nodes through the expanding lymphatic vessels to activate the effector lymphocytes. The latter was further collected to the kidney, which led to severer injury of renal tubular epithelial cells and peritubular capillaries, thus promoting the conversion of AKI to CKD. In this project, we intend to use the LYVE-1 conditional knockout or knockin transgenic mice on PROX1 potisive lymphatic endothelial cells to clarify the mechanism of ultra-low molecular and LYVE-1 to promote AKI to CKD by regulating lymphangiogenesis, and then activating acquired immune response. We will explore a new strategy to block or delay AKI's transition to CKD.