The role of NADPH oxidase in diabetic kidney disease: Mechanisms, isoforms, and therapeutic opportunities

Diabetic kidney disease (DKD) is a long-term complication of diabetes mellitus that significantly contributes to morbidity and mortality. In the multifactorial pathogenesis of DKD, NADPH oxidase (Nox) has recently been identified as a pivotal player in both the initiation and progression of disease. Nox enzymes are key producers of reactive oxygen species, perpetuating oxidative stress, which serves as a major trigger for renal cell injury. Thus, it is imperative to assess the precise role of Nox-mediated oxidative stress and the distinct Nox isoforms involved in DKD. Our review provides insights into the intricate mechanisms through which Nox and its subtypes contribute to the pathogenesis of DKD, emphasizing its involvement in glomerular (podocyte, mesangial, and endothelial) and tubular injury, as well as subsequent interstitial inflammation and fibrosis. In addition, we have summarized emerging therapeutic strategies targeting Nox inhibition to mitigate the progression of DKD, which offer focused clinical interventions for improved patient outcomes.