糖脂代谢紊乱、肾脏慢性炎性反应是糖尿病肾病（DN）、肾脏纤维化的重要病因病机，我们已证实SphK1/S1P通路的活化与糖尿病肾脏纤维化关系密切。近年来有充分证据表明胆汁酸膜受体TGR5具有显著调节糖脂代谢及抗炎作用。鉴于TGR5亦高表达于肾脏组织，TGR5能否抑制糖尿病状态下的肾脏炎性反应、阻抑肾脏纤维化的病理进程？以及该作用与影响SphK1/S1P通路的关系，值得高度关注。预实验结果显示：TGR5激动剂能明显抑制模型细胞与模型动物肾组织炎性、纤维化成分及S1P2的表达。本项目在此基础上，拟通过系统研究TGR5对模型细胞与模型动物肾组织ICAM-1及FN等炎性、纤维化成分的影响，明确TGR5对糖尿病肾脏纤维化的作用；进一步从影响SphK1/S1P通路、调节核因子NF-κB及AP-1的活性等，探讨其抗糖尿病肾脏纤维化的分子机制。为将TGR5作为抑制糖尿病肾脏纤维化、抗DN新靶点提供实验依据。

Glycolipid metabolism disorder and chronic renal inflammation are critical etiology and pathogenesis of diabetic nephropathy (DN) and renal fibrosis, and we have proved that the activation of SphK1/S1P pathway had close relationships with diabetic renal fibrosis. The bile acid membrane receptor TGR5 is confirmed to significantly regulate glycolipid metabolism and resist inflammation in recent years. Given that TGR5 is also highly expressed in kidney tissues, Whether TGR5 can inhibit renal inflammatory reaction and postpone the pathological process of renal fibrogenesis under the diabetic condition, and its relationship with SphK1/S1P pathway are worthy of investigation. Our preliminary experiments showed that TGR5 activator obviously inhibited the inflammatory and fibrotic components levels in both the cell model and kidney tissues of experimental animal as well as the expression of S1P2 receptor in the kidney tissues. Based on the above mentioned, the current program is undertaken to explore systematically the effects of TGR5 on the inflammatory and fibrotic components, such as ICAM-1, FN in the cell model and the kidney tissues of experimental animal, and to further investigate the molecular mechanism of TGR5 on regulating the SphK1/S1P pathway and modulating the transcriptional activities of nuclear factors NF-κB and AP-1 to provide experimental evidences and theoretical foundations for exploring TGR5 as a new target in the treatment of diabetic renal fibrosis and DN.