Uric Acid and Diabetic Retinopathy

Diabetic retinopathy (DR) is a potentially blinding complication of diabetes mellitus and the leading cause of blindness in adults. DR incidence is projected to rise with epidemic proportion causing a serious global health problem. The identification of new therapies as well as new diagnostic tools to allow early intervention are urgently needed. We have designed studies to demonstrate the novel hypothesis that enhanced production and accumulation of monosodium urate (MSU) in retinal cells contributes to DR induction and progression. Rationale for the proposed studies is provided by emerging evidence suggesting that accumulation of MSU contributes to the development of diabetes and its complications. Our preliminary data and evidence provided by the literature confirm this role for MSU in DR. MSU is the crystal form of uric acid (UA), a by-product of the purine catabolism. Increased intracellular production of UA/MSU alters cell homeostasis leading to oxidative stress, inflammation and, potentially, cell death. Our preliminary studies show that UA/MSU formation and accumulation in the diabetic human and rodent retina is significantly increased. Moreover, treatment of diabetic rats with hypouricemic drugs halts retinal inflammation and retinal blood barrier dysfunction. Much of UA/MS pathogenic effects have been attributed to its alarmin-like function in activating the nod-like pyrin 3 (NLRP3)- inflammasome to promote sterile inflammation. Our preliminary data show that UA/MSU exerts a synergistic activity with glucidic stress in promoting NLRP3-inflammasome activation and consequent production of interleukin-1beta (IL-1?). In addition, treatment of STZ-rats with hypouricemic drugs down-regulate inflammasome activation and IL-1? production further supporting the hypothesis of UA/MSU pathogenic role in DR. As part of purine metabolic processing, UA/MSU production could be impacted by dysfunction of adenosinergic and purinergic systems. This implies that MSU monitoring and/or modulation could also account/reflect changes in these systems. Based on this evidence we have designed studies to shed light on the molecular basis regulating MSU formation and mode of action in the diabetic retina and in retinal epithelial and endothelial cells, to: Aim 1) Determine the mechanisms of enhanced UA/MSU production and accumulation in the diabetic retina. Aim 2) Determine the mechanism of MSU pro-inflammatory effects in the diabetic retina Aim 3) Determine the long-term effects of hypouricemic drugs on diabetes-induced retinal neurovascular injury.