Abstract
Purpose :
Retinopathy of prematurity (ROP) is the leading cause of blindness in children globally. A key hallmark of ROP is the intricate and underexplored metabolic dysfunction resulting from early hyperglycemia and nutrient/hormone deprivation, which leads to abnormal retinal development. Emerging evidence suggests nutritional interventions may prevent developmental pathology of the retina. However, our knowledge of the metabolic responses occurring during early ROP in premature infants remain very limited. Here we utilized a combination of proteomics and metabolomics to investigate the underlying retinal metabolic shifts in mice with postnatal hyperglycemia-associated retinal vessel growth delay, modeling early ROP.
Methods :
Hyperglycemia was induced in neonatal C57BL/6J (WT) pups by intraperitioneal administration of streptozotocin (STZ) on postnatal day (P) 1 to P9. Quantitative mass spectrometry (MS) was utilized to perform proteomic (n=10) and metabolomic (n=12) analyses on pooled retina samples at P10. Bioinformatic analyses were used to determine protein-protein interactions and metabolic overrepresentation enrichment analysis to compare phenotypes. Both male and female mice were used. This work is compliant with ARVO’s Statement for the Use of Animals in Ophthalmic and Vision Research.
Results :
In STZ- vs vehicle-control treated WT mice, 63 metabolic enzymes we quantitatively measured and 9 citric acid cycle (TCA) proteins were upregulated (1.2 fold-change [FC]+, P<0.05). 147 metabolites were identified with 19 downregulated and 47 upregulated (1.2FC-5FC) resulting from hyperglycemia. Enrichment analysis (Metaboanalyst 5.0) of the differentially expressed metabolites revealed key metabolic pathways including glycolysis/gluconeogenesis (P<0.003) and TCA cycle (P<0.008), along with purine and pyrimidine metabolism (P<2.08E-7, P<1.47E-4, respectively) were modulated resulting from postnatal hyperglyemia.
Conclusions :
Our data indicate that hyperglycemia induces metabolic shifts in essential pathways necessary for normal retinal development. Further understanding and modulation of these pathways may prevent early ROP.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.