Modeling molecular level mechanisms of oxidative stress generation induced by agrochemicals in CKDu initiation

Abstract

Oxidative stress is identified as a primary factor contributing to the failure of renal function. The excessive generation of oxidative stress is observed in CKDu patients in many experiments. Agrochemicals are identified as a major inducer of oxidative stress. Oxidative stress is induced mainly by direct generation of ROS through enzyme activation and by depleting antioxidant enzymes. To study how toxic exposure to agrochemicals alters the oxidative stress level in CKDu, a mathematical model of the body’s Redox system was developed and simulated how toxic exposure to agrochemicals, particularly arsenic toxicity, increases oxidative stress in cells. This model was employed to study how the molecular mechanisms of ROS generation are affected in CKDu. The study explores how arsenic concentration levels alter the oxidative stress levels and molecular interactions involved. The model indicates that the mitochondrial electron transport chain complex III is the primary contributor to ROS production, which needs to be validated through wet lab experiments. Sensitivity analyses on the model revealed that parameters associated with superoxide production are susceptible to perturbations. Further analysis shows that enzyme-driven reactions, especially those involving superoxide generation, catalase, and glutathione peroxidase, are crucial in governing oxidative stress generation in CKDu. According to the sensitivity analysis results, both NOX (NADPH oxidase) and SOD2 (superoxide dismutase 2) appear to be promising drug targets.