MIF依赖性巨噬细胞在顺铂诱导的急性肾损伤中的作用

The role of MIF-dependent macrophages in cisplatin induced acute kidney injury

目的探讨巨噬细胞迁移抑制因子(MIF)依赖性巨噬细胞在顺铂诱导的急性肾损伤(AKI)中的作用和机制。方法MIF基因敲除(MIF-/-)小鼠被随机分为正常对照组(n=6)和实验组(n=18)。正常对照组小鼠尾静脉注射生理盐水,实验组小鼠腹腔注射顺铂建立AKI模型。建模6 h后小鼠被随机分为AKI模型组、巨噬细胞对照组和MIF-/-巨噬细胞组(每组n=6),尾静脉分别注射生理盐水、野生型C57BL/6J小鼠的巨噬细胞、MIF-/-小鼠的巨噬细胞。3 d后处死小鼠,收集血清和肾脏组织标本。评估肾功能、肾组织病理学改变以及肾组织中单核细胞趋化蛋白(MCP-1)和TNF-α的分布与表达,检测肾组织中Mincle、诱导型一氧化氮合酶(iNOS)、F4/80的蛋白表达。结果与AKI模型组相比,巨噬细胞对照组小鼠血清肌酐升高(P<0.001)、肾小管坏死加重(P<0.001),肾脏中MCP-1和TNF-α的蛋白表达增加(P均<0.01),M1型巨噬细胞增多(P<0.001)。与巨噬细胞对照组相比,MIF-/-巨噬细胞组小鼠血清肌酐降低(P<0.001),肾小管损伤减轻(P<0.001),肾脏中MCP-1和TNF-α的蛋白表达降低(P均<0.01),M1型巨噬细胞减少(P<0.001)。结论在顺铂诱导AKI的过程中,MIF通过激活Mincle促进巨噬细胞活化并增加炎性细胞因子的产生,导致肾脏炎症损伤加重。

Objective To investigate the role and mechanism of macrophage migration inhibitor(MIF)-dependent macrophages in cisplatin-induced acute kidney injury(AKI).Methods MIF gene knockout male mice were randomly divided into the normal control group(n=6)and experimental group(n=18).Mice in the normal control group were injected with saline via the tail vein.In the experimental group,the AKI mouse models were established by intraperitoneal injection of cisplatin.At 6 h after AKI model establishment,the mice were randomly divided into the AKI model group,macrophage control group,and MIF-/-macrophage group(n=6 in each group),which were injected with saline,macrophages from C57BL/6J mice and macrophages from MIF-/-mice through the tail vein,respectively.After 3-d feeding,the blood and renal tissue samples were collected.The renal function,pathological changes of renal tissues,the localization and expression of monocyte chemoattractant protein-1(MCP-1)and tumor necrosis factor-α(TNF-α)were evaluated.The expression levels of Mincle,inducible nitric oxide synthase(iNOS)and F4/80 proteins in the kidney were quantitatively detected.Results Compared with the AKI model group,the serum level of creatinine was significantly up-regulated(P<0.001),the renal tubular necrosis was significantly aggravated(P<0.001),the expression levels of MCP-1 and TNF-αproteins in the kidney were remarkably up-regulated(both P<0.01),and the ratio of M1 macrophages was significantly increased(P<0.001)in the macrophage control group.Compared with the macrophage control group,the serum level of creatinine was significantly down-regulated(P<0.001),the renal tubular necrosis was considerably alleviated(P<0.001),the expression levels of MCP-1 and TNF-αproteins in the kidney were remarkably down-regulated(both P<0.01),and the ratio of M1 macrophages was significantly decreased(P<0.001)in the MIF-/-macrophage group.Conclusion During the process of cisplatin-induced AKI,MIF promotes the activation of macrophages and increases the production of inflammatory cytokines by activating Mincle,which exacerbates the renal inflammatory injury.