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

Frontiers in Medicine

Medicine

Ming-Tsun Tsai¹  Chih-Ching Lin¹  Yeou-Guang Tsay²  Chin-Wei Kuo³  Hsiao-Wei Cheng³  Hsiang-Tsui Wang⁴  Dong-Hao Chen⁵ 

[1] Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan;School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan;Institute of Biochemistry and Molecular Biology, College of Life Science, National Yang Ming Chiao Tung University, Taipei, Taiwan;Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan;Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan;Institute of Food Safety and Health Risk Assessment, National Yang Ming Chiao Tung University, Taipei, Taiwan;Doctor Degree Program in Toxicology, Kaohsiung Medical University, Kaohsiung, Taiwan;Molecular Medicine Program, National Yang Ming Chiao Tung University, Taipei, Taiwan;

关键词: renal fibrosis;    acrolein;    pyruvate kinase M2;    hypoxia-inducible factor 1-alpha;    hydralazine;    carnosine;   

DOI  :  10.3389/fmed.2023.1151359

 received in 2023-01-26, accepted in 2023-02-22,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

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Copyright © 2023 Kuo, Chen, Tsai, Lin, Cheng, Tsay and Wang.