Downregulation of fatty acid binding protein 4 alleviates lipid peroxidation and oxidative stress in diabetic retinopathy by regulaging peroxisome proliferator-activated receptor γ-mediated ferroptosis

This study aims to explore the role of fatty acid binding protein 4 (FABP4) in diabetic retinopathy (DR), and to elucidate the potential regulatory mechanism. We firstly developed a mouse model of DR by injection with streptozocin (STZ) into C57BL/6 male mice and a cell model of DR by induction of high glucose (HG) to ARPE-19 cells. BMS309403, an inhibitor of FABP4, was employed for treatment. The blood glucose in vivo was monitored and the histological changes of retinal tissues were observed by hematoxylin and eosin staining and Evans blue assay. The expression level of FABP4 was detected by western blot and lmmunohistochemical staining. The critical factors related to lipid peroxidation and oxidative stress were detected using their commercial kits, respectively. Prussian blue staining, iron content assay and thiobarbituric add-reactive substances (TBARS) assay were conducted to evaluate ferroptosis. As a result, FABP4 was elevated in retina and serum of STZ-induced mice and in HG-induced ARPE-19 cells. BMS309403 treatment notably alleviated reduced blood glucose, reduced histological damage, and vascular permeability. In addition, BMS309403 treatment inhibited lipid peroxidation, oxidative stress, and ferroptosis both in vivo and in vitro. Furthermore, BMS309403 promoted the activation of peroxisome proliferator-activated receptor y (PPARy). GW9662 (an inhibitor of PPARy) or Erastin (an inducer of ferroptosis) partially weakened the suppressive effects of BMS309403 on HG-induced lipid peroxidation, oxidative stress and ferroptosis. Taken together, FABP4 inhibition alleviates lipid peroxidation and oxidative stress in DR by regulating PPARy-mediated ferroptosis. [GRAPHICS] .

Automated summary

The study investigates the role of FABP4 in diabetic retinopathy (DR) and its regulation mechanism. Through mouse and cell models, it is found that inhibiting FABP4 can alleviate the development of DR and reduce lipid peroxidation and oxidative stress through regulating the PPARy-mediated ferroptosis pathway.