Sunday, May 18, 2025
5/18/2025
Molecular Mechanisms of Severe Diabetic Retinopathy - Abstract: Diabetic retinopathy (DR) is the most frequent cause of new cases of blindness in working-age adults. Current standard treatments include anti-VEGF therapy and laser photocoagulation for severe non-proliferative and proliferative retinopathy and macular edema. No effective treatment is available to prevent the progression of DR to the devastating advanced stages in patients who fail to achieve good glycemic control. Understanding the mechanisms underlying the early pathological features of DR and developing a long-term treatment to prevent severe retinopathy are urgent unmet needs. Our proposed research aims to address these mechanistic and translational gaps by targeting an important pathway that leads to vascular damage in DR. Our prior work has demonstrated that NADPH oxidase 4 (Nox4), which is the predominant form of NADPH oxidase that generates reactive oxygen species in retinal vascular endothelial cells (EC), is upregulated in diabetes. Upregulation of Nox4 promotes retinal vascular leakage and capillary loss in the diabetic retina; however, the mechanisms are poorly understood. Our new study identified that upregulation of Nox4 leads to retinal EC senescence. These senescent cells (SnCs) secrete senescence-associated secretory phenotype (SASP) factors and produce high levels of extracellular hydrogen perioxide (H2O2), which act on pericytes inducing pericyte cell death. Further, we observed increased EC senescence and pericyte loss in the retina of EC-specific Nox4 transgenic mice. These findings strongly suggest Nox4-mediated EC senescence as a novel pathogenic pathway in DR progression by inducing pericyte loss; loss of pericytes in turn destabilizes endothelial barrier and disrupts capillary structure resulting in microaneurysm formation, vascular leakage, and acellular capillary formation. In the proposed studies, we will elucidate novel signaling pathways by which Nox4 upregulation induces EC senescence and explore the mechanisms by which EC senescence promotes pericyte loss and vascular damage in DR. We hypothesize that the accumulation of SnCs in retinal vessels resulting from Nox4 upregulation and other factors plays a critical role in DR progression. Using our new- generation senolytics, we aim to develop a long-term treatment by eliminating SnCs in the diabetic retina via systemic administration. Our recent work has demonstrated that these novel senolytics have potent senolytic activity and minimal toxicity on platelets and thus can be used systemically. This will not only overcome the platelet toxicity of current senolytics which can only be given via intravitreal injection but will likely offer a better and longer therapeutic effect to prevent DR progression because it can clear SnCs in tissues other than the retina, reduce systemic inflammation, and be administrated repeatedly as needed. Therefore, successful completion of the proposed studies will provide novel insights into the mechanisms of endothelial dysfunction and pericyte loss in DR and more importantly, could lead to an effective and long-term treatment to prevent DR progression in diabetic patients.
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