补体C5a及其受体介导糖尿病肾病炎症和纤维化损伤的作用及机制研究

Inflammation and fibrosis play important roles in the pathogenesis of diabetic nephropathy (DN), which is the most common complication and leading cause of mortality associated with diabetes. Infiltrated immune cells and intrinsic kidney cells are reported to be the most important factors contributing to inflammation and fibrosis mediated acceleration of DN progression. Complement 5a (C5a)/complement 5a receptor (C5aR) signaling pathway is extensively involved in mediating inflammation and fibrosis, but its role and mechanism in contributing to the development of DN remains largely unclear. Our preliminary findings demonstrated that C5a expression was notably intensified in both tubule cells from DN patients’ biopsies and serum from DN mouse model, meanwhile advanced glycation end products could up-regulate C5a expression in cultured proximal tubular epithelial cells. Furthermore, we found that activated C5a/C5aR signaling pathway could crosstalk with other classical signaling pathways to facilitate synthesis and production of TGF-β in kidney and subsequently promote the development of renal fibrosis, while administration of C5a inhibitor could reverse this effect by blocking TGF-β driven renal fibrosis and improve renal function in DN mouse model. Accordingly, we propose that activated C5a/C5aR signaling pathway contributes to the progression of renal inflammation and fibrosis in DN through recruiting and activating multiple infiltrated immune cells, as well as shifting various intrinsic kidney cells into inflammatory and fibrotic phenotype. To test this hypothesis, we will adopt comprehensive and diversified experimental plans and techniques to clarify the role and mechanism of C5a/C5aR signaling pathway in the development of DN, aimed to provide theoretical evidence for exploring new therapeutic targets for DN.

炎症和纤维化在DN发病过程中起着重要作用，而补体C5a及其受体C5aR可广泛调控炎症和纤维化反应，但是C5a/C5aR信号轴在DN发病过程中的作用和机制尚未完全阐明。我们前期研究证实，C5a在DN患者肾小管上皮细胞和DN小鼠血清中表达升高，糖基化终末产物可上调肾小管上皮细胞内的C5aR，活化的C5a/C5aR信号轴可促进DN小鼠肾内TGF-β的合成和分泌以及肾脏纤维化进展，而使用C5a抑制剂可下调TGF-β的表达从而减轻肾脏纤维化并改善肾功能。综合前期研究成果，我们提出假设：C5a/C5aR信号轴是DN肾内调控炎症和纤维化反应的重要途径，它可以募集和激活免疫细胞并诱导肾固有细胞向炎症纤维化表型转化，从而促进DN病理损伤进展。为验证该假说，本项目拟通过细胞、分子和动物模型三个层次的交叉渗透研究深入阐明C5a/C5aR信号轴在DN发病过程中的作用及分子机制，为寻找DN新型治疗方法提供理论依据。

补体C5a/C5aR信号轴与糖尿病肾病(DN)的发病机制有关，糖尿病肾病是糖尿病最主要的并发症之一。作为机体天然免疫的重要组成部分，C5a/C5aR信号轴的激活与糖尿病肾病发病过程中的慢性炎症密切相关。先前的研究证明了C5aR缺陷在DN小鼠模型中对肾脏的保护作用，然而，在疾病进展过程中，C5a/C5aR信号轴在肾内免疫细胞和肾固有细胞中的作用尚不明确。本研究中，我们成功构建了骨髓细胞或肾实质细胞C5aR缺陷的嵌合体小鼠，用于STZ诱导的DN模型。研究结果表明，骨髓细胞中的 C5aR 通过1) 破坏脂质代谢，2)诱导炎症和纤维化，3)在DN的病理异常中起主要作用。体外研究进一步阐明，在体外培养的巨噬细胞中，C5a/C5aR信号轴的激活可直接诱导炎症反应，而近端肾小管上皮细胞中的C5a/C5aR信号轴可被高糖刺激激活。总之，本研究的结果为C5a/C5aR信号轴作为DN的潜在抗炎治疗靶点提供了支持性证据。