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Inhibition of miR‐144‐3p enhances Nrf2 and protects against retinal degeneration

Retinal pigment epithelial (RPE) cells are consistently exposed to high levels of pro‐oxidant and inflammatory stimulation. As such under normal conditions, the antioxidant machinery in this cell type is one of the most efficient in the entire body. In aging and disease however, these defense mechanisms often fail, leaving RPE susceptible to damage, which contributes, to degeneration of the outer retina. Thus, understanding better the mechanisms that regulate antioxidant responses is critically important. Oxidative stress increases the expression of several miRNAs, known as oxidative stress‐responsive miRNAs however, the mechanisms by which these miRs regulate expression of antioxidant target genes and related signaling is not completely understood. In the present study, we evaluated the role of the redox sensitive microRNA, miR‐144‐3p, in antioxidant signaling in RPE cells. In our cell culture model system, miR‐144‐3p expression was up‐regulated in response to pro‐oxidant stimuli. Over‐expression of miR‐144‐3p attenuated expression of Nrf2 and related antioxidant genes thereby increasing the susceptibility of RPE cells to further oxidative damage. Thus, we hypothesized that inhibiting miR‐144‐3p might be protective against RPE/retinal damage. To test this, 8‐wk old male C57BL/6J mice were treated with single dose of 50 mg/kg sodium iodate (i.p.) to induce retinal degeneration. However, sub‐retinal injection of miR‐144‐3p antagomir (5μg/kg) preserved retinal integrity, decreased oxidative stress, limited apoptosis and enhanced the expression of antioxidant genes in this mouse model of retinal degeneration. Our present study establishes inhibition of miR‐144‐3p as a potential therapeutic target for prevention and treatment of degenerative retinal diseases in which RPE is prominently affected.