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MCC950 targets the ROS-NEK7-NLRP3 axis to improve type 2 diabetic retinopathy
1Dalian University Affiliated Xinhua Hospital, Dalian, 116035, Liaoning, China.
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.
Insights
MCC950 effectively treats diabetic retinopathy in rats by targeting the ROS-NEK7-NLRP3 pathway. A 1 mM concentration of MCC950 demonstrated optimal efficacy in improving retinal structure and reducing inflammation.
Area of Science:
- Ophthalmology
- Immunology
- Pharmacology
Background:
- Diabetic retinopathy (DR) is a major complication of type 2 diabetes mellitus (T2DM).
- NLRP3 inflammasome activation, driven by reactive oxygen species (ROS) and NEK7, plays a critical role in DR pathogenesis.
- MCC950 is a specific NLRP3 inflammasome inhibitor, but its concentration-dependent effects on DR require detailed investigation.
Purpose of the Study:
- To quantify the effects of varying intravitreal MCC950 concentrations (0.01, 0.1, 1, 10 mM) on retinal structure and NLRP3 inflammasome signaling in a rat model of T2DM.
- To determine the optimal concentration of MCC950 for ameliorating T2DM-induced retinal pathology.
- To elucidate the role of the ROS-NEK7-NLRP3 pathway in MCC950's retinoprotective effects.
Main Methods:
- Intravitreal injections of graded MCC950 concentrations were administered to streptozotocin-induced T2DM rats.
- Quantitative assessments included retinal histopathology, apoptosis, oxidative stress (ROS levels), and NLRP3 inflammasome pathway markers (NEK7, NLRP3, Cleaved Caspase-1, IL-1β, IL-18).
- Correlation analyses were performed to assess relationships between ROS, NEK7, and NLRP3 expression.
Main Results:
- A 1 mM concentration of MCC950 significantly improved retinal histopathological alterations, reduced apoptosis, and mitigated oxidative stress in T2DM rats (p<0.05).
- MCC950 suppressed NLRP3 inflammasome activation by disrupting the NEK7-NLRP3 interaction, leading to decreased levels of Cleaved Caspase-1, IL-1β, and IL-18 (p<0.001).
- MCC950 treatment significantly lowered retinal ROS levels, with a strong positive correlation observed between ROS and NEK7 expression (r=0.8857, p<0.05).
Conclusions:
- MCC950, particularly at 1 mM, effectively ameliorates T2DM-induced retinal damage by targeting the ROS-NEK7-NLRP3 axis.
- The drug inhibits ROS-mediated NEK7 upregulation and subsequent NLRP3 inflammasome activation.
- MCC950 treatment attenuates pathological damage, oxidative stress, inflammation, and apoptosis in the diabetic retina.
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