Oxidative Stress in the Pathophysiology of Chronic and Diabetic Kidney Disease: Molecular Mechanisms, Biomarkers, and Antioxidant Therapeutic Strategies

Despite considerable breakthroughs in renoprotective medicines, chronic kidney disease (CKD) and diabetic kidney disease (DKD) remain the predominant causes of end-stage renal disease and cardiovascular morbidity. Growing evidence shows that oxidative stress is not simply a result of renal injury but a crucial pathogenic element interconnecting metabolic dysregulation, mitochondrial dysfunction, inflammation, endothelial dysfunction, and fibrogenesis. Physiological ROS mediate cellular signaling, mitochondrial homeostasis, and adaptive responses. Persistent redox imbalance, by contrast, results in excessive production of ROS by dysfunctional mitochondria, NADPH oxidases, uremic toxins, and hyperglycemia-driven metabolic pathways that drive self-amplifying oxidative circuits that accelerate nephron loss. This review provides a comprehensive synthesis of the existing knowledge on the molecular causes of oxidative stress in CKD and DKD, with a focus on disease-specific pathways such as mitochondrial dysfunction, AGE–RAGE signaling, metabolic memory, insulin resistance, and lipotoxicity. It also describes cell-specific oxidative injury in podocytes, mesangial cells, tubular epithelial cells, and endothelial cells, and how these contribute to glomerular dysfunction, tubulointerstitial fibrosis, and disease progression. Emerging redox-targeted strategies, such as mitochondria-targeted antioxidants, NADPH oxidase inhibitors, Nrf2 activators, and sirtuin modulation, are reviewed in terms of experimental rationale and clinical evidence. We discuss established renoprotective therapies, such as RAAS inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists, separately to distinguish demonstrated clinical benefits from the still incompletely established contribution of redox mechanisms. The clinical use of circulating and urinary oxidative stress biomarkers is also critically evaluated. Finally, we discuss new research directions in precision redox medicine, including cell-specific antioxidant delivery, redox-sensitive molecular imaging, integration of multi-omics, artificial intelligence-assisted biomarker discovery, and human-relevant translational models, as well as the current stages of development and barriers to clinical application. The present review combines mechanistic evidence with biomarker and translational studies to prioritize research in biomarker-informed risk stratification and mechanism-guided redox therapies in CKD and DKD. However, their clinical utility remains to be proven and requires independent validation and prospective evidence of improved patient outcomes. These advances provide a foundation for biomarker-informed risk stratification and mechanism-guided therapy in CKD and DKD, but clinical use requires further validation and evidence of improved patient outcomes.