Work

Podocyte SIRPα reduction in diabetic nephropathy aggravates podocyte injury by promoting pyruvate kinase M2 nuclear translocation

Year: 2024

Type: article

Abstract: Podocyte injury is a critical event in the pathogenesis of diabetic nephropathy (DN). Hyperglycemia, oxidative stress, inflammation, and other factors contribute to podocyte damage in DN. In this study, we demonstrate that signaling regulatory protein alpha (SIRPα) plays a pivotal role in regulating the metabolic and immune homeostasis of podocytes. Deletion of SIRPα in podocytes exacerbates, while transgenic overexpression of SIRPα alleviates, podocyte injury in experimental DN mice. Mechanistically, SIRPα downregulation promotes pyruvate kinase M2 (PKM2) phosphorylation, initiating a positive feedback loop that involves PKM2 nuclear translocation, NF-κB activation, and oxidative stress, ultimately impairing aerobic glycolysis. Consistent with this mechanism, shikonin ameliorates podocyte injury by reducing PKM2 nuclear translocation, preventing oxidative stress and NF-κB activation, thereby restoring aerobic glycolysis. • Podocyte SIRPα is downregulated in DN, and whereas transgenic SIRPα reduces podocyte damage, its deletion exacerbates it. • SIRPα deficiency promoted PKM2 nuclear translocation, which triggers NF-κB activation and oxidative stress. • Shikonin relieves SIRPα-deficient podocyte damage by preventing PKM2 nuclear translocation.

Source: Redox Biology

DOI: 10.1016/j.redox.2024.103439