#5322 RENAL AEROBIC GLYCOLYSIS AND LOCAL LACTATE PRODUCTION IN AKI

Kidney is a high energy-consuming organ depending on fatty acid β-oxidation (FAO) to fulfil energy supply. During various biological stresses in AKI, FAO shuts down, and the aerobic glycolysis is enhanced. In this study, we aimed to investigate the effect of aerobic glycolysis and local lactate production in AKI.

A maleic acid (MA) induced AKI model (MA-AKI) was established by MA intraperitoneally (i.p.) in C57BL/6J mice and sacrificed after 24h. The renal function in MA-AKI mice was damaged, accompanied by proximal tubular injury and mitochondrial dysfunction. RNA sequencing revealed a relative increase in glycolytic enzymes (HK1, PKM and PFKP) mRNA levels in the AKI phase. The protein level of glycolysis-related enzymes was also elevated with increased urinary lactate significantly (0.25±0.10 versus 8.60±0.74 mmol/L, P<0.0001) in MA-AKI. Furthermore, glycolysis inhibitor 2-DG was administrated after 2h of MA injection, which improved the renal function (indicated by decreased serum creatinine (Scr), 33.52±2.78 versus 57.15±4.81 μmol/L, P<0.001), proximal tubular histopathological injuries and mitochondrial dysfunction in MA-AKI. Mechanistically, we observed a significant positive correlation between the Scr and urinary lactate levels (R² = 0.78, P < 0.0001). In order to examine the role of lactate in AKI, the mice were pretreated with oxamate, an inhibitor of lactate dehydrogenase A (LDHA), and the level of Scr (59.18±5.83 versus 28.82±3.41 μmol/L, P<0.0001) was mitigated, with the reduction of urinary lactate (8.60±0.74 versus 4.90±0.98 mmol/L, P<0.01).

Our study demonstrated that inhibition of aerobic glycolysis to protect kidney function in MA-AKI might be via reducing lactate accumulation.