Hydroxychloroquine suppresses anti-GBM nephritis via inhibition of JNK/p38 MAPK signaling
Hydroxychloroquine suppresses anti-GBM nephritis via inhibition of JNK/p38 MAPK signaling
复制标题
DOI：
10.1007/s10157-022-02285-y
复制
发表时间：
2022-10
影响因子：
2.3
通讯作者：
Miki Torigoe;Y. Obata;H. Inoue;Kenta Torigoe;A. Kinoshita;T. Koji;H. Mukae;T. Nishino
中科院分区：
文献类型：
--
作者：
Miki Torigoe;Y. Obata;H. Inoue;Kenta Torigoe;A. Kinoshita;T. Koji;H. Mukae;T. Nishino
背景抗肾小球基底膜（抗GBM）肾炎以肾小球新月体形成为特征，由于预后不良，需要早期治疗。羟氯喹 (HCQ) 是一种抗疟药，具有已知的免疫调节、抗炎和自噬抑制作用；它被认为可以治疗系统性红斑狼疮等自身免疫性疾病。然而，其对抗GBM肾炎的作用仍不清楚。本研究探讨HCQ对大鼠抗GBM肾炎的影响。方法7周龄雄性WKY大鼠给予抗GBM血清诱导抗GBM肾炎。诱导肾炎后第0天至第7天施用HCQ或载体对照。通过测量血清肌酐、蛋白尿和血尿来评估肾功能。通过PAS染色和Masson三色染色评估肾脏组织学变化，并通过ED-1染色评估巨噬细胞的浸润。通过蛋白质印迹法评估丝裂原激活蛋白激酶（MAPK），通过尿样酶联免疫吸附测定评估趋化因子和炎症细胞因子。结果HCQ治疗抑制了肾功能的下降。组织学上，从第1天开始观察到毛细血管外和毛细血管内增殖，而从第3天开始观察到纤维蛋白样坏死和ED-1阳性细胞。抗GBM肾炎大鼠表现出高水平的单核细胞趋化蛋白-1和肿瘤坏死因子-α。 HCQ 治疗后这些变化被显着抑制。此外，HCQ还抑制JNK/p38 MAPK磷酸化。结论HCQ通过抑制JNK/p38 MAPK活化发挥抗炎作用，从而减弱抗GBM肾炎，表明其具有抗GBM肾炎的治疗潜力。
BackgroundAnti-glomerular basement membrane (anti-GBM) nephritis, characterized by glomerular crescent formation, requires early treatment because of poor prognosis. Hydroxychloroquine (HCQ) is an antimalarial drug with known immunomodulatory, anti-inflammatory, and autophagy inhibitory effects; it is recognized in the treatment of autoimmune diseases such as systemic lupus erythematosus. However, its effect on anti-GBM nephritis remains unknown. In this study, we investigated the effect of HCQ on anti-GBM nephritis in rats.MethodsSeven-weeks-old male WKY rats were administered anti-GBM serum to induce anti-GBM nephritis. Either HCQ or vehicle control was administered from day 0 to day 7 after the induction of nephritis. Renal function was assessed by measuring serum creatinine, proteinuria, and hematuria. Renal histological changes were assessed by PAS staining and Masson trichrome staining, and infiltration of macrophages was assessed by ED-1 staining. Mitogen-activated protein kinase (MAPK) was evaluated by western blotting, while chemokine and inflammatory cytokines were evaluated by enzyme-linked immunosorbent assay using urine sample.ResultsHCQ treatment suppressed the decline in renal function. Histologically, extracapillary and intracapillary proliferations were observed from day 1, while fibrinoid necrosis and ED-1 positive cells were observed from day 3. Rats with anti-GBM nephritis showed high levels of monocyte chemotactic protein-1 and tumor necrosis factor-α. These changes were significantly suppressed following HCQ treatment. In addition, HCQ suppressed JNK/p38 MAPK phosphorylation.ConclusionHCQ attenuates anti-GBM nephritis by exerting its anti-inflammatory effects via the inhibition of JNK/p38 MAPK activation, indicating its therapeutic potential against anti-GBM nephritis.