Down-Regulation of PPARα through MicroRNA-Associated Mechanism in Diabetic Retinopathy

Abstract

Purpose : Peroxisome proliferator-activated receptor-alpha (PPARα) is a crucial transcription factor regulating numerous gene expressions implicated in lipid metabolism, glucose metabolism and insulin resistance. Two longitudinal clinical studies reported that administration of fenofibrate, a specific PPARα agonist, showed robust beneficial effects on diabetic retinopathy (DR) in type 2 diabetes patients. Our recent studies showed that PPARα possesses anti-inflammatory and anti-apoptotic functions, and down-regulation of PPARα in diabetic retina is associated with pathogenic features of DR. In the last ARVO meeting, we reported that over-expression of microRNA-21 (miR-21) is implicated in the PPARα down-regulation in DR. In the present study, we examined the functional role of miR-21 in retinal inflammation and retinal cell apoptosis due to the down-regulation of PPARα in DR.

Methods : PPARα expression, inflammation and apoptosis in the retina of 6 month-old db/db and double knockout (dKO; Leptin receptor (db/db) and miR-21) mice were examined by qRT-PCR, Western blotting and ELISA. Similarly, miR-21 inhibitor and its negative control inhibitor were packed in nanoparticle and injected into vitreous space of 5 month-old db/db mice, and PPARα expression, retinal inflammation and retinal cell apoptosis were evaluated at 6 month-old. Furthermore, in addition to retinal inflammation, the impact of miR-21 on retinal neovascularization was evaluated with oxygen-induced retinopathy (OIR) model using miR-21 KO mice.

Results : Expression levels of PPARα were significantly higher in the retina of dKO mice, whereas retinal inflammation and retinal cell apoptosis were significantly lower compared to age-matched db/db mice. Similarly, delivery of miR-21 inhibitor into vitreous space prevented the down-regulation of PPARα and reduced retinal inflammation and apoptosis. Furthermore, retinal neovascularization and retinal inflammation were ameliorated in the retina of miR-21 KO mice with OIR.

Conclusions : The present study showed that diabetes-induced over-expression of miR-21 in the retina is responsible, at least in part, for down-regulation of PPARα in DR. Our studies also suggest that knock-down of miR-21 in the retina offers a therapeutic benefit to ameliorate inflammatory responses, oxidative stress and neuronal apoptosis in DR.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.