Zhao Yu, Guo Yinfeng, Jiang Yuteng, Zhu Xiaodong, Liu Yuqiu, Zhang Xiaoliang
Institute of Nephrology, Zhong Da Hospital, Southeast University, School of Medicine, Nanjing, Jiangsu, 210009, China.
Institute of Nephrology, Zhong Da Hospital, Southeast University, School of Medicine, Nanjing, Jiangsu, 210009, China.
Biochem Biophys Res Commun. 2017 Dec 9;494(1-2):42-50. doi: 10.1016/j.bbrc.2017.10.088. Epub 2017 Oct 21.
Imbalance of M1/M2 macrophages phenotype activation is a key point in diabetic nephropathy (DN). Macrophages mainly exhibit M1 phenotype, which contributes to the inflammation and fibrosis in DN. Studies indicate that autophage plays an important role in M1/M2 activation. However, the effect of mitophage on M1/M2 macrophage phenotype transformation in DN is unknown. This study investigates the role of mitophage on macrophage polarization in DN. In vivo experiments show that macrophages are exhibited to M1 phenotype and display a lower level of mitophagy in the kidney of streptozocin (STZ)-induced diabetic rats. Additionally, inducible nitric oxide synthase (iNOS) expression is positive correlated with the P62 expression, while negative correlated with LC3. Electronic microscope analysis shows mitochondria swelling, crista decrease and lysosome reduction in DN rats compared with NC rats. In vitro, RAW264.7 macrophages switch to M1 phenotype under high glucose conditions. Mitophagy is downregulated in such high glucose induced M1 macrophages. Furthermore, macrophages tend to switch to the M1 phenotype, expressing higher iNOS and TNF-α when impair mitophagy by 3-MA. Rapamycin, an activator of mitophagy, signifcantly blocks high-glucose induced M1 makers (iNOS and TNF-α) expression, meanwhile enhances M2 makers (MR and Arg-1) expression. These results demonstrate that mitophage participates in the regulation of M1/M2 macrophage phenotype in diabetic nephropathy.
M1/M2巨噬细胞表型激活失衡是糖尿病肾病（DN）的关键因素。巨噬细胞主要表现为M1表型，这会导致DN中的炎症和纤维化。研究表明自噬在M1/M2激活中起重要作用。然而，线粒体自噬对DN中M1/M2巨噬细胞表型转化的影响尚不清楚。本研究探讨线粒体自噬在DN中巨噬细胞极化中的作用。体内实验表明，在链脲佐菌素（STZ）诱导的糖尿病大鼠肾脏中，巨噬细胞表现为M1表型且线粒体自噬水平较低。此外，诱导型一氧化氮合酶（iNOS）表达与P62表达呈正相关，而与LC3呈负相关。电子显微镜分析显示，与正常对照大鼠相比，DN大鼠的线粒体肿胀、嵴减少且溶酶体减少。在体外，RAW264.7巨噬细胞在高糖条件下转变为M1表型。在这种高糖诱导的M1巨噬细胞中线粒体自噬下调。此外，当用3-MA抑制线粒体自噬时，巨噬细胞倾向于转变为M1表型，iNOS和TNF-α表达更高。线粒体自噬激活剂雷帕霉素显著阻断高糖诱导的M1标志物（iNOS和TNF-α）表达，同时增强M2标志物（MR和Arg-1）表达。这些结果表明线粒体自噬参与糖尿病肾病中M1/M2巨噬细胞表型的调节。
