SGLT2抑制剂通过TGFβ2和JAK-STAT协同调控巨噬细胞-肌成纤维细胞转换（MMT）抗肾脏纤维化作用及机制研究

抗肾脏纤维化，延缓肾功能下降，是慢性肾脏病（CKD）治疗的世界难题。SGLT2抑制剂为糖尿病肾病的治疗开辟了新前景，非糖尿病CKD是否也受益于SGLT2抑制剂成为研究热点。前期研究显示SGLT2抑制剂（Empa）干预5/6肾切大鼠，具有抗肾纤维化保护肾功能作用。scRNA-Seq分析发现5/6肾切大鼠M2型巨噬细胞和肌成纤维细胞亚群异常增加，差异基因的IPA调控网络提示TGFβ2协同JAK-STAT致肾脏纤维化；Empa干预降低了M1型巨噬细胞JAK1表达，M2型巨噬细胞亚群下降。因此，推测Empa可能调控了巨噬细胞-肌成纤维细胞转换（MMT），起抗肾纤维化保护肾功能作用，此过程可能受TGFβ2和JAK-STAT协同调控。本课题拟通过scRNA-Seq、流式细胞方法，体外实验探索Empa通过调控MMT抗肾纤维化的分子机制。本研究将为SGLT2抑制剂治疗非糖尿病CKD提供理论依据。

Among the treatment of chronic kidney disease (CKD), the anti-renal fibrosis and postpone of the renal function is a worldwide difficult problem. SGLT2 inhibitors have opened up new prospects for the treatment of diabetic nephropathy. Whether non-diabetic CKD also benefits from SGLT2 inhibitors has become a research hotspot. Previous studies showed that inhibitor (Empagliflozin) with anti-renal fibrosis and renal function protection in 5/6 nephrectomy rats. Furthermore, scRNA-Seq analysis found that the clusters of M2 macrophage and myofibroblast significantly increased in untreated 5/6 nephrectomy rats，and the IPA regulatory network of differential genes suggests that TGFβ2 cooperates with JAK-STAT to induce renal fibrosis. The gene expression of JAK1 reduced in M1 macrophage, cluster of M2 macrophage and myofibroblast significantly decreased in 5/6 nephrectomy rats with Empa treatment. Therefore, we speculate that Empa may regulate the macrophage-myofibroblast transition (MMT) and play a role in preventing renal fibrosis and protecting renal function. This process may be coordinated by TGFβ2 and JAK-STAT. Therefore, this project intends to use scRNA-Seq, cell flow cytometry; and perform in vitro experiments to explore the molecular mechanism of Empa's anti-kidney fibrosis and renal function protection by regulating MMT. The study will provide a theoretical basis for the application of SGLT2 inhibitors in non-diabetic CKD.