Tian Jihua, Chen Jingshu, Sun Qiuyue, Huang Taiping, Xu Huanyu, Wang Jing, Ma Zhijie
Department of Microbiology and Immunology, School of Basic Medicine, Shanxi Medical University, Taiyuan, 030001, China.
Academy of Medical Sciences, Shanxi Medical University, Taiyuan, 030001, China.
Inflammation. 2024 Aug 7. doi: 10.1007/s10753-024-02118-y.
Diabetic kidney disease (DKD) is the most significant complication in diabetic patients, ultimately leading to renal fibrosis. The most important manifestation of DKD is the epithelial-mesenchymal transition (EMT) of renal tubular cells, which can lead to renal fibrosis and inflammatory injury in special situations. Sphingosine 1-phosphate (S1P) is involved in various signal transduction pathways and plays a role through G protein-coupled receptors. Research has demonstrated that blocking the S1P / S1PR2 pathway inhibits inflammation and fibrosis. However, the interaction between S1P/S1PR1 and the pathophysiology of EMT remains ambiguous. The purpose of this study was to investigate the mechanism of S1P/S1PR1 on high glucose (HG)-induced renal EMT. We found that HG markedly increased the S1P and EMT marker levels in renal tubular epithelial cells. At the same time, HG could stimulate NF-κB/ROS/NLRP3 expression, but these phenomena were reversed after blocking S1PR1. In mice models of DKD, FTY720 (S1P antagonist) could significantly improve renal function and reduce the infiltration of inflammatory cells. ROS, as well as NLPR3 inflammasome, were markedly decreased in the treatment group. FTY720 inhibits extracellular matrix synthesis and improves renal fibrosis. In brief, the HG stimulates S1P/S1PR1 synthesis and activates the S1P/S1PR1 pathway. Through the S1P/S1PR1 pathway, activates NF-κB, promotes ROS generation and NLRP3 inflammasome activation, and ultimately causes EMT.
糖尿病肾病（DKD）是糖尿病患者最严重的并发症，最终会导致肾纤维化。DKD最重要的表现是肾小管上皮细胞的上皮-间质转化（EMT），在特殊情况下可导致肾纤维化和炎性损伤。1-磷酸鞘氨醇（S1P）参与多种信号转导途径，并通过G蛋白偶联受体发挥作用。研究表明，阻断S1P/S1PR2途径可抑制炎症和纤维化。然而，S1P/S1PR1与EMT病理生理学之间的相互作用仍不明确。本研究旨在探讨S1P/S1PR1对高糖（HG）诱导的肾EMT的作用机制。我们发现HG显著增加肾小管上皮细胞中S1P和EMT标志物水平。同时，HG可刺激NF-κB/ROS/NLRP3表达，但阻断S1PR1后这些现象得到逆转。在DKD小鼠模型中，FTY720（S1P拮抗剂）可显著改善肾功能并减少炎性细胞浸润。治疗组中ROS以及NLPR3炎性小体明显减少。FTY720抑制细胞外基质合成并改善肾纤维化。简而言之，HG刺激S1P/S1PR1合成并激活S1P/S1PR1途径。通过S1P/S1PR1途径，激活NF-κB，促进ROS生成和NLRP3炎性小体激活，最终导致EMT。
