Mitophagy regulates macrophage phenotype in diabetic nephropathy rats.

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.