Crosstalk between MIR-96 and IRS/PI3K/AKT/VEGF cascade in hRPE cells; A potential target for preventing diabetic retinopathy

• Published in: PloS one Vol. 19; no. 9; p. e0310999
• Main Authors: Hosseinpoor, Zeynab, Soheili, Zahra-Soheila, Davari, Maliheh, Latifi-Navid, Hamid, Samiee, Shahram, Samiee, Dorsa
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 30.09.2024
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Analysis; Biology and Life Sciences; Calcium phosphates; Cell culture; Cell Line; Data mining; Diabetes; Diabetes mellitus; Diabetic retinopathy; Diabetic Retinopathy - genetics; Diabetic Retinopathy - metabolism; Diabetic Retinopathy - pathology; Edema; Enzymes; Eye; Eye diseases; Eye disorders; Forkhead Box Protein O1 - genetics; Forkhead Box Protein O1 - metabolism; FOXO1 protein; Gene expression; Gene Expression Regulation; Gene regulation; Genes; Genetic aspects; Genetic engineering; Glaucoma; Humans; Insulin; Insulin Receptor Substrate Proteins - genetics; Insulin Receptor Substrate Proteins - metabolism; Kinases; Life sciences; Medicine and Health Sciences; Metabolism; MicroRNA; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Online data bases; Phosphatidylinositol 3-Kinases - metabolism; Plasmids; Polymerase chain reaction; Prevention; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Research and Analysis Methods; Retina; Retinal cells; Retinal Pigment Epithelium - metabolism; Retinal Pigment Epithelium - pathology; Retinopathy; Signal Transduction; Substrates; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Visual perception; Visual system; Iran; United States > US; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0310999

Regulation of visual system function demands precise gene regulation. Dysregulation of miRNAs, as key regulators of gene expression in retinal cells, contributes to different eye disorders such as diabetic retinopathy (DR), macular edema, and glaucoma. MIR-96, a member of the MIR-183 cluster family, is widely expressed in the retina, and its alteration is associated with neovascular eye diseases. MIR-96 regulates protein cascades in inflammatory and insulin signaling pathways, but further investigation is required to understand its potential effects on related genes. For this purpose, we identified a series of key target genes for MIR-96 based on gene and protein interaction networks and utilized text-mining resources. To examine the MIR-96 impact on candidate gene expression, we overexpressed MIR-96 via adeno-associated virus (AAV)-based plasmids in human retinal pigment epithelial (RPE) cells. Based on Real-Time PCR results, the relative expression of the selected genes responded differently to overexpressed MIR-96. While the expression levels of IRS2, FOXO1, and ERK2 (MAPK1) were significantly decreased, the SERPINF1 gene exhibited high expression simultaneously. pAAV-delivered MIR-96 had no adverse effect on the viability of human RPE cells. The data showed that changes in insulin receptor substrate-2 (IRS2) expression play a role in disrupted retinal insulin signaling and contribute to the development of diabetic complications. Considered collectively, our findings suggest that altered MIR-96 and its impact on IRS/PI3K/AKT/VEGF axis regulation contribute to DR progression. Therefore, further investigation of the IRS/PI3K/AKT/VEGF axis is recommended as a potential target for DR treatment.