Exploring Angiotensin II and Oxidative Stress in Radiation-Induced Cataract Formation: Potential for Therapeutic Intervention

Abstract

Radiation-induced cataracts (RICs) represent a significant public health challenge, particularly impacting individuals exposed to ionizing radiation (IR) through medical treatments, occupational settings, and environmental factors. Effective therapeutic strategies require a deep understanding of the mechanisms underlying RIC formation (RICF). This study investigates the roles of angiotensin II (Ang II) and oxidative stress in RIC development, with a focus on their combined effects on lens transparency and cellular function. Key mechanisms include the generation of reactive oxygen species (ROS) and oxidative damage to lens proteins and lipids, as well as the impact of Ang II on inflammatory responses and cellular apoptosis. While the generation of ROS from water radiolysis is well established, the impact of Ang II on RICs is less understood. Ang II intensifies oxidative stress by activating type 1 receptors (AT1Rs) on lens epithelial cells, resulting in increased ROS production and inflammatory responses. This oxidative damage leads to protein aggregation, lipid peroxidation, and apoptosis, ultimately compromising lens transparency and contributing to cataract formation. Recent studies highlight Ang II's dual role in promoting both oxidative stress and inflammation, which accelerates cataract development. RICs pose a substantial public health concern due to their widespread prevalence and impact on quality of life. Targeting Ang II signaling and oxidative stress simultaneously could represent a promising therapeutic approach. Continued research is necessary to validate these strategies and explore their efficacy in preventing or reversing RIC development.

Keywords: angiotensin II; lens transparency; oxidative stress; radiation-induced cataracts; therapeutic intervention.

Figure 1

Five major mechanisms mediating Ang II-dependent RICF. We discuss the five RICF mechanisms connected to both the RAS signaling pathway and the IR-induced ROS. Each of the five mechanisms is derived from the interplay between radiation-dependent enhancement of Ang II signaling and ROS. While AT1R mediates the activities of Ang II, MasR counters the Ang II-induced phenotypes via interactions with Ang 1–7. We suggest that a combination of MasR agonism and ROS suppression may be considered a fruitful direction for RIC countermeasure development.

Figure 2

Holistic view of key molecules and signaling events from IR to cataract formation. This schematic captures the activities and events connecting IR to RICF. X represents a small molecule countermeasure we are developing against RICF. As a bi-functional, single small molecular entity, X was designed to tame both Ang II signaling and ROS production, two major activities contributing to RICF. In preliminary animal-based studies, X demonstrated promising activities in suppressing RICF [65]. Future work will be required to further develop X as a bona fide RICF countermeasure.