Arachidonic Acid Disrupts PKM2-Linked Glycolysis-Related Metabolism and Exacerbates PAN-Induced Podocyte Injury.

Minimal change disease (MCD) frequently relapses, and infection is one of the most common clinical triggers. Arachidonic acid (AA), an inflammatory lipid mediator released during tissue injury and infection, has been implicated in podocyte injury, but its contribution to metabolic dysfunction in MCD remains unclear. Here, we investigated whether AA aggravates PAN-induced podocyte injury and examined the involvement of pyruvate kinase M2 (PKM2)-associated metabolic dysfunction. In a puromycin aminonucleoside (PAN)-induced rat model, AA exposure increased serum AA levels, aggravated proteinuria, reduced nephrin expression, promoted foot-process effacement and exacerbated mitochondrial dysfunction. AA was also associated with reduced PKM1 and PKM2 abundance, increased PKM2 (Tyr105) phosphorylation, decreased pyruvate kinase activity and lower pyruvate, lactate and ATP levels. In cultured human podocytes, AA intensified PAN-induced cytoskeletal disruption, mitochondrial dysfunction, oxidative stress and apoptosis. Pharmacological activation of PKM2 with TEPP-46 partially restored PK-associated metabolic activity, improved mitochondrial readouts and attenuated podocyte injury in vitro. These findings suggest that AA exacerbates PAN-induced podocyte injury in association with PKM2-associated metabolic dysfunction and mitochondrial stress.