MicroRNA-184 promotes differentiation of the retinal pigment epithelium by targeting the AKT2/mTOR signaling pathway

Abstract

Dedifferentiation of retinal pigment epithelium (RPE) cells is a crucial contributing factor to the pathology of retinal degenerative diseases, including age-related macular degeneration (AMD). Herein, we aim to reveal the roles of microRNAs (miRNAs) in RPE dedifferentiation and seek for potential therapeutic targets. Based on the microarray data, miR-184 was sorted out as the most up-regulated signature along with the differentiation from human induced pluripotent stem cells (hiPSC) to RPE cells, suggesting its potential promotive role in RPE differentiation. In vitro study indicated that miR-184 insufficiency suppressed RPE differentiation, typified by reduction of RPE markers, and promoted cell proliferation and migration. The role of miR-184 in maintaining regular RPE function was further proved in zebrafish studies. We also noticed that miR-184 expression was reduced in the macular RPE-choroid from a donor with RPE dysfunction compared to a healthy control. We next demonstrated that RAC-beta serine/threonine-protein kinase (AKT2) was a direct target for miR-184. MiR-184 promoted RPE differentiation via suppression of AKT2/mammalian target of rapamycin (mTOR) signaling pathway. We also found that AKT2 was up-regulated in macular RPE-choroid of the donor with RPE dysfunction and dry AMD patients. Taken together, our findings suggest that miR-184 insufficiency is involved in the pathogenesis of dry AMD. MiR-184 promotes RPE differentiation via inhibiting the AKT2/mTOR signaling pathway. MiR-184 based supplementary therapeutics and mTOR blocker, like rapamycin, are prospective options for AMD treatment.

MicroRNA-Related Genetic Variants Are Associated With Diabetic Retinopathy in Type 1 Diabetes Mellitus

“…MicroRNA 449a and 449b have been found in retinal tissues of mice. 29,30 In an oxygeninduced DR mouse model, microRNA 449a was significantly downregulated, which is in keeping with a protective role against DR. 30 MicroRNA 449b has not been reported in human vitreous; however, the studies investigating vitreous micro-RNAs are few, and a small number of specimens (fewer than five PDR samples) have been analyzed. [26][27][28] The angiogenesis pathway that microRNA 449b regulates is the E2F pathway.…”

miR-184 Inhibits Tumor Invasion, Migration and Metastasis in Nasopharyngeal Carcinoma by Targeting Notch2

“…Mature miR-184, which contains 22 nucleotides, exhibits expression patterns specific to tissue and developmental stages [12]. It has been extensively reported that miR-184 activity participates in the control of a wide range of biological functions and processes such as changes in response to DOR activation in the Rat Liver Under Prolonged Hypoxia [13].…”

LncRNA ZNF503-AS1 promotes RPE differentiation by downregulating ZNF503 expression

“…Retinal pigment epithelium (RPE) is a monolayer of cuboidal, polarized, and pigmented epithelial cells located in the outer retina between photoreceptors and choroidal vessels. 1 , 2 , 3 RPE forms a part of the blood/retina barrier, secrets multiple growth factors, and is crucial in maintaining regular retinal functions. 2 , 3 , 4 Dysfunction and depletion of RPE cells are involved in multiple retinal degenerations, including age-related macular degeneration (AMD).…”

“… 1 , 2 , 3 RPE forms a part of the blood/retina barrier, secrets multiple growth factors, and is crucial in maintaining regular retinal functions. 2 , 3 , 4 Dysfunction and depletion of RPE cells are involved in multiple retinal degenerations, including age-related macular degeneration (AMD). 2 , 5 , 6 , 7 AMD is a universal leading cause for irreversible vision loss in people aged over 55.…”