Pyruvate kinase M2 modification by a lipid peroxidation byproduct acrolein contributes to kidney fibrosis

Abstract

Renal fibrosis is a hallmark of diabetic nephropathy (DN) and is characterized by an epithelial-to-mesenchymal transition (EMT) program and aberrant glycolysis. The underlying mechanisms of renal fibrosis are still poorly understood, and existing treatments are only marginally effective. Therefore, it is crucial to comprehend the pathophysiological mechanisms behind the development of renal fibrosis and to generate novel therapeutic approaches. Acrolein, an α-,β-unsaturated aldehyde, is endogenously produced during lipid peroxidation. Acrolein shows high reactivity with proteins to form acrolein-protein conjugates (Acr-PCs), resulting in alterations in protein function. In previous research, we found elevated levels of Acr-PCs along with kidney injuries in high-fat diet-streptozotocin (HFD-STZ)-induced DN mice. This study used a proteomic approach with an anti-Acr-PC antibody followed by liquid chromatography–tandem mass spectrometry (LC–MS/MS) analysis to identify several acrolein-modified protein targets. Among these protein targets, pyruvate kinase M2 (PKM2) was found to be modified by acrolein at Cys358, leading to the inactivation of PKM2 contributing to the pathogenesis of renal fibrosis through HIF1α accumulation, aberrant glycolysis, and upregulation of EMT in HFD-STZ-induced DN mice. Finally, PKM2 activity and renal fibrosis in DN mice can be reduced by acrolein scavengers such as hydralazine and carnosine. These results imply that acrolein-modified PKM2 contributes to renal fibrosis in the pathogenesis of DN.

Targeting pyruvate kinase M2 for the treatment of kidney disease

“…The modification at Cys358 by acrolein leads to PKM2 inactivation and aberrant glycolysis to promote renal fibrosis progression in high-fat diet-streptozotocin-induced diabetic kidney disease (DKD) mice. Treatment with acrolein scavengers (hydralazine and carnosine) obviously attenuates PKM2 activity and renal fibrosis ( Kuo et al, 2023 ). Inhibiting neddylation modification by MLN4924 treatment induces tetramerization and activates PKM2 to increase glycolysis against cancer cell growth ( Zhou et al, 2019 ).…”