Targeting posttranslational modifications of oxidative stress pathways for the treatment of diabetic nephropathy.

Abstract

Diabetic nephropathy (DN), a major microvascular complication of diabetes, is the leading cause of chronic kidney disease (CKD). Oxidative stress has emerged as a central driver of DN, making its associated signaling pathways promising therapeutic targets. When reactive oxygen species (ROS) exceed the cell's antioxidant capacity, they disrupt homeostasis and trigger inflammation, apoptosis, necrosis, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. In the kidneys, these events accelerate fibroblast activation and collagen deposition, leading to fibrosis, glomerulosclerosis, and progressive loss of function. Recent studies identify post-translational modifications (PTMs) as key regulators in this process. By altering protein structure, function, and interactions, PTMs modulate many of the pathological mechanisms underlying DN. Targeting oxidative stress pathways regulated by PTMs therefore offers a promising therapeutic approach. In this review, we first introduce the role of PTMs in DN and outline the contribution of oxidative stress to disease progression. We then examine how PTMs regulate oxidative stress pathways, highlight novel modifications with potential relevance to DN, and discuss emerging therapeutic strategies targeting these pathways.