Danny Varghese

Background:  Diabetic retinopathy (DR) is a leading cause of vision impairment among adults globally, with prevalence rates expected to rise alongside increasing diabetes incidence.¹ This condition results from prolonged hyperglycemia and dyslipidemia, leading to oxidative stress and mitochondrial damage within the retinal microvascular endothelium.^1,2,3 Vision loss caused by leaky retinal endothelial cell barrier and diabetic macular edema can occur in the initial stage of non-proliferative DR and late proliferative DR. However, therapeutic strategies to prevent or treat the initial retinal microvascular damage and DR progression are lacking. Recent studies suggest that Rac1, a small GTPase, plays a significant role in the pathogenesis of DR by modulating oxidative stress and mitochondrial function.⁴ Despite substantial research, gaps remain in understanding the early molecular mechanisms contributing to DR and specifically how Rac1 influences mitochondrial integrity and function in the retinal endothelium.^2,4,5

Objective(s):  This review aimed to delineate the role of Rac1 in mitochondrial dysfunction and its contribution to the progression of DR. With this, identifying potential early biomarkers and therapeutic targets may be possible.

Search Methods:  A comprehensive literature review was conducted using databases such as PubMed and Web of Science from 2018 to 2024. Key search terms included “Rac1,” “diabetic retinopathy,” “mitochondrial dysfunction,” and “oxidative stress.” MeSH terms such as “Diabetes Mellitus,” “Retinal Diseases,” and “Mitochondrial Damage” were also utilized to refine the search.

Results:  Studies have shown that the activation of Rac1 leads to increased production of reactive oxygen species (ROS) primarily through NADPH oxidase complexes, which precede mitochondrial damage and the onset of DR. The activation of Rac1 has been associated with changes in mitochondrial DNA integrity, reduction in mitochondrial function, and increased retinal endothelial cell apoptosis.^4,6 Further, specific single nucleotide polymorphisms (SNPs) in the Rac1 gene have been associated with an elevated risk of DR, suggesting genetic predispositions that exacerbate Rac1’s pathological effects.⁷ Experimental models using diabetic rats and human retinal endothelial cells have shown that inhibition of Rac1 activity can mitigate mitochondrial damage and reduce markers of early DR progression.⁶

Conclusion:  The results of these studies underscore Rac1 as a pivotal factor in the development of DR through its role in mitochondrial dysfunction. Targeting Rac1 for therapeutic intervention may provide a novel approach to prevent or delay the progression of DR in diabetic patients.^4,6 Future research should explore the molecular mechanisms of Rac1 activation and its interactions with mitochondrial pathways in the retinal endothelium to develop targeted therapies. Further studies are also needed to validate the clinical relevance of Rac1 SNPs as biomarkers for susceptibility to DR.

Works Cited:

1. Vujosevic S, Aldington SJ, Silva P, et al. Screening for diabetic retinopathy: new perspectives and challenges. Lancet Diabetes Endocrinol. 2020;8(4):337-347. doi:10.1016/s2213-8587(19)30411-5.
2. Tan T, Wong TY. Diabetic retinopathy: Looking forward to 2030. Front Endocrinol (Lausanne). 2023;13. doi:10.3389/fendo.2022.1077669
3. Kang Q, Yang C. Oxidative stress and diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications. Redox Biol. 2020;37:101799. doi:10.1016/j.redox.2020.101799
4. Kowluru RA. Retinopathy in a Diet-Induced Type 2 Diabetic Rat model and role of epigenetic modifications. Diabetes. 2020;69(4):689-698. doi:10.2337/db19-1009.
5. Kowluru RA, Mohammad G. Epigenetics and Mitochondrial Stability in the Metabolic Memory Phenomenon Associated with Continued Progression of Diabetic Retinopathy. Sci. Rep. 2020;10(1):1-13. doi:10.1038/s41598-020-63527-1
6. Kowluru RA, Radhakrishnan R, Mohammad G. Regulation of Rac1 transcription by histone and DNA methylation in diabetic retinopathy. Sci. Rep. 2021;11(1):1-10. doi:10.1038/s41598-021-93420-4
7. Azarova I, Klyosova E, Polonikov A. Single nucleotide polymorphisms of the RAC1 gene as novel susceptibility markers for neuropathy and microvascular complications in Type 2 diabetes. Biomedicines. 2023;11(3):981. doi:10.3390/biomedicines11030981