Oxaloacetate Restores HIF-1α-Mediated Mitochondrial Homeostasis to Counter Tubulointerstitial Injury in Diabetic...

Renal tubular injury, one of the most critical events in diabetic kidney disease (DKD), plays a pivotal role in the progression of the disease. Metabolic reprogramming of renal tubular cells emerges as a prominent pathological feature, yet its underlying molecular mechanisms remain incompletely understood.

We established a streptozotocin-induced mouse model of diabetes. Metabolomic analysis was then used to characterise DKD-specific metabolic alterations. To test the functional consequence of a metabolic intervention, DKD mice received intraperitoneal injections of oxaloacetate (OAA). Furthermore, molecular docking and cellular thermal shift assays were used to elucidate the molecular mechanisms underlying OAA's effects on renal tubular injury, which were further validated in HK-2 cells exposed to high glucose. Finally, a specific pharmacological inhibitor was applied to study the relevant signalling pathway.

Metabolomic profiling identified a marked decrease in OAA, a key tricarboxylic acid (TCA) cycle intermediate, in injured renal tubular cells. OAA supplementation significantly attenuated tubulointerstitial injury, as evidenced by reduced tubular cell damage, fibrosis, and macrophage infiltration. Moreover, restored mitochondrial homeostasis was observed in DKD mice after OAA treatment. Mechanistically, we found that OAA inhibited prolyl hydroxylase domain 2 (PHD2), an essential regulator of hypoxia-inducible factor-1α (HIF-1α), thereby stabilising mitochondrial homeostasis. Furthermore, pharmacological inhibition of HIF-1α abolished the protective effects of OAA, confirming the involvement of the PHD2/HIF-1α axis.

OAA ameliorates renal tubulointerstitial injury in DKD by restoring mitochondrial homeostasis through the PHD2/HIF-1α axis.