Dapagliflozin may attenuate podocyte injury in diabetic kidney disease through inhibition of lactate-mediated H4K12 lactylation

Introduction Podocyte injury is central to diabetic kidney disease (DKD). Metabolic reprogramming, particularly lactate accumulation, may drive podocyte injury via epigenetic mechanisms, yet this process remains poorly understood. This study aimed to clarify lactate's role in podocyte injury and explore the protective effects of dapagliflozin. Methods We retrospectively analyzed plasma lactate levels in healthy individuals, patients with diabetes, and DKD patients, and examined correlations with proteinuria. Subsequently, db/db mice and cultured podocytes were used to explore mechanisms of lactate-induced podocyte injury and potential protective effects of dapagliflozin in vivo and in vitro. Results Plasma lactate levels were analyzed in 66 healthy controls, 150 patients with diabetes, and 152 patients with DKD. Lactate concentrations were significantly higher in DKD patients compared with both diabetic patients and healthy controls. In DKD patients, lactate levels were positively correlated with serum creatinine and albuminuria. Logistic regression analysis identified hypertension, plasma lactate, white blood cell count, glycated hemoglobin, and serum creatinine as independent risk factors for DKD. Notably, dapagliflozin treatment significantly reduced plasma lactate levels in DKD patients. In diabetic mice and high-glucose-stimulated podocytes, marked lactate accumulation accompanied by increased histone H4 lysine 12 lactylation (H4K12la) was observed, indicating lactate-driven epigenetic regulation. In contrast, dapagliflozin treatment reduced lactate production and H4K12la levels, attenuated proteinuria, and ameliorated podocyte injury. Conclusions Lactate contributes to podocyte injury in DKD at least in part through promoting H4K12 lactylation. Dapagliflozin exerts renoprotective effects by attenuating this lactate-mediated epigenetic pathway, highlighting a potential therapeutic mechanism beyond glucose control.