| Summary: | Diabetic kidney disease (DKD) is a common and severe complication of diabetes mellitus. If left untreated, DKD can advance to end stage renal disease that requires either dialysis or kidney replacement. While numerous mechanisms underlie the pathogenesis of DKD, oxidative stress driven by NADH/NAD<sup>+</sup> redox imbalance and mitochondrial dysfunction have been thought to be the major pathophysiological mechanism of DKD. In this review, the pathways that increase NADH generation and those that decrease NAD<sup>+</sup> levels are overviewed. This is followed by discussion of the consequences of NADH/NAD<sup>+</sup> redox imbalance including disruption of mitochondrial homeostasis and function. Approaches that can be applied to counteract DKD are then discussed, which include mitochondria-targeted antioxidants and mimetics of superoxide dismutase, caloric restriction, plant/herbal extracts or their isolated compounds. Finally, the review ends by pointing out that future studies are needed to dissect the role of each pathway involved in NADH-NAD<sup>+</sup> metabolism so that novel strategies to restore NADH/NAD<sup>+</sup> redox balance in the diabetic kidney could be designed to combat DKD.
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