Monosodium Urate Contributes to Retinal Inflammation and Progression of Diabetic Retinopathy

Abstract

We have investigated the contributing role of monosodium urate (MSU) to the pathological processes associated with the induction of diabetic retinopathy (DR). In human postmortem retinas and vitreous from donors with DR, we have found a significant increase in MSU levels that correlated with the presence of inflammatory markers and enhanced expression of xanthine oxidase. The same elevation in MSU levels was also detected in serum and vitreous of streptozotocin-induced diabetic rats (STZ-rats) analyzed at 8 weeks of hyperglycemia. Furthermore, treatments of STZ-rats with the hypouricemic drugs allopurinol (50 mg/kg) and benzbromarone (10 mg/kg) given every other day resulted in a significant decrease of retinal and plasma levels of inflammatory cytokines and adhesion factors, a marked reduction of hyperglycemia-induced retinal leukostasis, and restoration of retinal blood-barrier function. These results were associated with effects of the hypouricemic drugs on downregulating diabetes-induced levels of oxidative stress markers as well as expression of components of the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome such as NLRP3, Toll-like receptor 4, and interleukin-1β. The outcomes of these studies support a contributing role of MSU in diabetes-induced retinal inflammation and suggest that asymptomatic hyperuricemia should be considered as a risk factor for DR induction and progression.

Role of Endothelial ADAM17 in Early Vascular Changes Associated with Diabetic Retinopathy

“…Leukocyte adhesion to the retinal endothelium was evaluated as described previously [38]. Following the induction of deep anesthesia (ketamine/xylazine, 80 and 12 mg/kg of body weight, respectively), the chest cavity was opened, and a 22-gauge perfusion cannula was introduced into the left ventricle.…”

“…Immunostaining of retinal sections was performed as described [38]. Mouse eyes were enucleated, embedded in optimal cutting temperature mounting medium (Tissue-Tek, Torrance, CA, USA), frozen on dry ice, and cryostat sectioned (10 µm).…”

Novel inhibitory effects of dotinurad, a selective urate reabsorption inhibitor, on urate crystal-induced activation of NLRP3 inflammasomes in macrophages

“…Serum levels of both IL-1β and IL-18 are elevated in diabetic patients with nephropathy 35) , which indicates that there is activation of NLRP3 inflammasomes in diabetic kidney disease. In retinas of diabetic patients, elevated uric acid is associated with activation of NLRP3 inflammasomes 11) . In general, hyperuricemia in patients with diabetes or metabolic syndrome is caused by excess renal reabsorption of urate through URAT1 and the sodium-coupled monocarboxylate transporter SMCT1, which are stimulated by insulin 19) .…”

“…Clinical studies suggest that asymptomatic hyperuricemia is not only a risk factor for gout and chronic kidney disease 4) , but also for cardiovascular disease 5) , metabolic syndrome 6) , and diabetic complications 7) . Recently, the NLRP3 inflammasome has been reported to play a pivotal role in the onset of such diseases [8][9][10][11] . Therefore, uric acid lowering agents may prevent the development of NLRP 3 inflammasome-related diseases.…”

Dysregulation of the NLRP3 Inflammasome in Diabetic Retinopathy and Potential Therapeutic Targets

“…Lysosomal damage is a known activator of the NLRP3 , 13,67 ; possibly through the release of Cathepsin B into the cytoplasm following lysosomal rupture. 23 Lysosomal stress can be precipitated by numerous means such as declining autophagy efficiency, 68 irritants such as uric acid (UA), 69 and aging. 70 UA is the byproduct of purine metabolism and at serum levels above 356 (μmol/L), it forms into the NLRP3 detectable DAMP, monosodium urate (MSU) crystals.…”