Oxidative Stress-Induced Dysregulation of Cytoskeletal Dynamics and Vesicular Trafficking in Retinal Pigment Epithelium: Implications for Retinal Degeneration

Introduction

The cytoskeleton and trafficking pathway play a pivotal role in maintaining cellular homeostasis, particularly in retinal pigment epithelium (RPE), which is essential for photoreceptor functionality. Dysfunction in these pathways is increasingly recognized as a contributor to retinal degenerative diseases, such as Retinitis Pigmentosa (RP). This study explores transcriptomic alterations in RPE cells under oxidative stress conditions induced by oxidized low-density lipoproteins (oxLDLs).

Methods

Human RPE cells were exposed to oxLDL (100 µg/ml), and transcriptomic analyses were conducted across three time points (0h, 3h, and 6h). RNA-seq was utilized for differential gene expression profiling, and data were analyzed using Gene Set Enrichment Analysis (GSEA) to highlight significantly altered pathways. Focus was given to cytoskeleton-related genes and their association with vesicular trafficking and signal transduction.

Results

Significant changes were observed in genes regulating cytoskeleton integrity, vesicle trafficking, and motor protein function. The key findings include the 1) dysregulation of Retinitis Pigmentosa GTPase Regulator (RPGR), impairing ciliary transport; 2) alterations in actin filament organization and microtubule stabilization, disrupting cellular polarity and vesicular transport; 3) upregulation of genes like FAM161A and RP1, linked to microtubule binding and photoreceptor disk morphogenesis; and 4) progressive collapse of intermediate filaments and junctional complexes affecting RPE--photoreceptor interactions.

Conclusion

Cytoskeleton-related pathways undergo extensive remodeling under oxidative stress, contributing to the pathophysiology of RP. Disruption in vesicular trafficking and cytoskeletal organization underscores the mechanistic link between oxidative stress and retinal degeneration. This study identifies novel targets within the cytoskeleton pathway, providing a foundation for therapeutic exploration in retinal disorders