PGF (Placental growth factor) is a member of the vascular endothelial growth factor (VEGF) sub-family a crucial factor in angiogenesis and vasculogenesis. Mechanisms by which PlGF expression is regulated remain to be investigated in diabetic retinopathy DR. However, the underlying molecular mechanisms that PlGF, mediates in the early complications at non-proliferative DR remain mostly elusive. Here we have applied an LC-MS/MS-based label-free quantification proteomic approach to PlGF ablation in the retinal tissues from mouse strains (Akita, PlGF-/- and Akita.PlGF-/-). The proteomes of retinal tissues were extracted, digested by the Trypsin/LysC enzyme and subsequently analyzed by a Q-Exactive hybrid Quadrupole-Orbitrap mass spectrometer. We have performed normalization by the Z-score method, correlation by Pearson correlation coefficient and identified differentially expressed proteins in four comparisons. The gene ontology, functional pathways, and protein-protein network interaction analysis suggested that Gnb1, Gnb2, Gnb4, Gnai2, Gnao1, Snap2 and Gngt1 proteins are involved in insulin resistance pathways, which are down-regulated/ no significant in PlGF ablation in Akita diabetics (Akita.PlGF-/- vs. Akita), up-regulated in Akita vs. C57, PlGF-/- vs. C57. Prdx6, Map2 are involved in antioxidant activity and neural protection pathways respectively, which are up-regulated in Akita.PlGF-/- vs. Akita. Our proteomics outcomes anticipated that down-regulated of insulin resistance pathways, up-regulation of antioxidant and neuroprotection proteins might epitomize the potential mechanisms of anti-PlGF therapies in the treatment of DR.