MCC950 targets the ROS-NEK7-NLRP3 axis to improve type 2 diabetic retinopathy

Abstract 1 mM of MCC950 targets the ROS-NEK7-NLRP3 axis to ameliorate T2DM in rats and exhibits peak efficacy in improving retinopathy. It has been found that the specific inhibitor MCC950 can alleviate diabetic retinopathy by inhibiting NLRP3 inflammasome, but its concentration-dependent efficacy on retinal pathology needs to be explored. The aim of this study was to quantify the effects of intravitreal injection of graded concentrations of MCC950 (0.01, 0.1, 1,10 mM) on retinal structure and NLRP3 inflammasome signalling in type 2 diabetic male rats, and to reveal that 1 mM MCC950 may exert optimal retinoprotective effects by down-regulating the NEK7-NLRP3 pathway. Type 2 diabetic male rats induced by streptozotocin were administered intravitreal injections of MCC950 at varying concentrations (0.01, 0.1, 1, 10 mM). Quantitative assessments revealed that a concentration of 1 mM MCC950 markedly improved retinal histopathological alterations ( p < 0.05) and modulated retinal apoptosis and oxidative stress to a considerable degree ( p < 0.05). On a mechanistic level, MCC950 suppressed NLRP3 inflammasome activation by disrupting the interaction between NEK7 and NLRP3 (manifested by the down-regulation of pathway-associated protein expression, p <0.05) and a strong positive correlation between NEK7 and NLRP3 protein expression ( r = 0.62, p = 0.19); inhibited the activation of the NLRP3 inflammasome (manifested by reduced levels of Cleaved Caspase-1, IL-1β, and IL-18, p < 0.001). There was a positive correlation between the intensity of ROS fluorescence and the fluorescence expression of NEK7 ( r = 0.8857, p < 0.05), with MCC950 treatment significantly lowering retinal ROS levels at the 1 mM concentration. In conclusion, MCC950 inhibits ROS-mediated NEK7 upregulation, NLRP3 activation, and attenuates pathological damage, oxidative stress, retinal inflammation, and apoptosis in type 2 diabetic retina via ROS-NEK7-NLRP3 pathway.