Liu Benquan, Nie Jiayi, Liang Hua, Liang Zijie, Huang Jiangju, Yu Wenqiang, Wen Shihong
Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, 528000, China.
Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, 528000, China; Translational Medicine Institute of Anesthesiology and Perioperative Medicine, The First People's Hospital of Foshan, Foshan, 528000, China.
Eur J Pharmacol. 2021 Jun 15;901:174097. doi: 10.1016/j.ejphar.2021.174097. Epub 2021 Apr 19.
Renal fibrosis is the common pathological hallmark of chronic kidney disease, and SET domain containing lysine methyltransferase 7 (SETD7) promote considerably renal fibrosis. However, the signaling mechanisms underlying SETD7 driving renal fibrosis are not fully understood. Here, we investigated the role of SETD7 in M2 macrophages-myofibroblasts transition and the myeloid fibroblasts activation in folic acid and obstruction-induced renal fibrosis. Mice treated with PFI-2, an inhibitor of SETD7, presented less bone marrow-derived myofibroblasts, fewer CD206+/α-smooth muscle actin + cells and developed less renal fibrosis (P＜0.01). Furthermore, SETD7 inhibition reduced the infiltration of inflammatory cells and decreased the production of pro-inflammatory cytokines and chemokines in the kidneys after folic acid treatment (P＜0.01). Finally, SETD7 inhibition suppressed the accumulation of NF-κB p65+ cells in folic acid nephropathy (P＜0.01). Taken together, SETD7 mediates M2 macrophages-myofibroblasts transition, bone marrow-derived myofibroblasts activation, and inflammation response in the development of renal fibrosis.
肾纤维化是慢性肾脏病的常见病理标志，含SET结构域的赖氨酸甲基转移酶7（SETD7）在很大程度上促进肾纤维化。然而，SETD7驱动肾纤维化的信号传导机制尚未完全明确。在此，我们研究了SETD7在叶酸和梗阻诱导的肾纤维化中M2巨噬细胞-肌成纤维细胞转化及骨髓来源的成纤维细胞激活中的作用。用SETD7抑制剂PFI-2处理的小鼠骨髓来源的肌成纤维细胞减少，CD206+/α平滑肌肌动蛋白+细胞减少，肾纤维化程度减轻（P＜0.01）。此外，抑制SETD7可减少叶酸处理后肾脏中炎性细胞浸润，并降低促炎细胞因子和趋化因子的产生（P＜0.01）。最后，抑制SETD7可抑制叶酸肾病中NF-κB p65+细胞的积聚（P＜0.01）。综上所述，SETD7在肾纤维化发生发展过程中介导M2巨噬细胞-肌成纤维细胞转化、骨髓来源的成纤维细胞激活及炎症反应。
