The Role of Glycolysis in Diabetic Kidney Disease

Diabetic kidney disease (DKD) is a leading cause of end-stage kidney disease worldwide and remains associated with high morbidity and mortality. In DKD, glycolytic reprogramming is triggered by hyperglycemia, hypoxia, oxidative stress, and inflammatory activation, which converge to drive metabolic imbalance. These stimuli promote excessive glycolytic flux, lactate accumulation, and diverse post-translational modifications, thereby reinforcing pathological reactions such as epithelial–mesenchymal transition, inflammation, and renal fibrosis. Accumulating evidence indicates that glycolytic alterations in DKD are highly cell type-specific. In podocytes, impaired glycolysis disrupts actin cytoskeletal integrity, promotes foot process fusion/effacement, and compromises the glomerular filtration barrier, ultimately leading to proteinuria. In tubular epithelial cells, glycolysis drives mesenchymal transformation and fibrogenesis, and engages in crosstalk with macrophages. In mesangial cells, glycolysis promotes mesangial cell hypertrophy and contributes to mesangial expansion. Mechanistically, central regulators including HIF-1α and PKM2, are modulated through glycolysis associated mechanisms, linking glycolysis to mitochondrial dysfunction, pathological cellular phenotypes, and DKD progression. Therapeutically, SGLT2 inhibitors have been clinically applied for DKD and kidney protection. Clinical studies further show that they can suppress maladaptive glycolytic activation in human metabolic analysis. Collectively, current evidence highlights glycolysis as a key driver of DKD and therapeutic targets for DKD management.