Abstract
Purpose :
Clinical studies have shown a causative role for asymptomatic hyperuricemia and progression of diabetic retinopathy (DR). Our previous work in an experimental model of DR demonstrated the pro-oxidative and pro-inflammatory activity of monosodium urate (MSU), the sodium salt and circulating form of uric acid, in the diabetic retina. To better characterize MSU mechanisms of action in the diabetic retina, we investigated the effects of MSU modulation on the expression profile of different microRNAs (miRs).
Methods :
MiR arrays were conducted on retinal extracts of streptozotocin-induced diabetic rats (STZ-rats) at 8 weeks of hyperglycemia and were compared to age-matched normoglycemic rats (Control) and to STZ-rats that received the hypouricemic drug allopurinol (STZ+All, 50mg/Kg, p.o.). QPCR, using specific sets of primers, was used to validate the expression pattern of miRs of interest in the retinal extracts of all experimental groups.
Results :
Our arrays showed several miRs and miR clusters that were modulated by diabetes and All. MiR-21 and miR-155 levels were augmented in the diabetic retinas and were downregulated by All. These miRs are involved in MSU-induced pyroptosis. In addition, we found that the miR-34a and miR-Let-7d-5p, that were increased in the diabetic retina, were downregulated by All. Both these miRs are linked to p53 function and have been involved in vascular senescence (miR-34a) and fibrosis (miR-Let-7d-5p). Finally, we observed that in the diabetic retina miR-Let-7d-3p was down-regulated and its expression was restored by All. On the contrary to its guide strand, this miR possesses anti-inflammatory abilities.
Conclusions :
Our results underscore the contribution of MSU and its ability to elicit epigenetic challenges to the diabetic retina leading to inflammation and fibrosis. In addition, our data suggest the regulation of Let-7d miRs biogenesis (5p and 3p) as part of MSU pathogenic function in the diabetic retina.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.