Integrated Multi-Omics Reveal PDK4-Mediated Mitochondrial Dysfunction in Renal Ischemia-Reperfusion Injury

Abstract (Background) Renal ischemia reperfusion injury (IRI) represents the predominant etiology of acute kidney injury, yet its molecular events and underlying mechanism remain incompletely elucidated. (Methods) To investigate the integrative and dynamic pathophysiology of renal IRI, we conducted a comprehensive multi-omics (transcriptomics, proteomics and metabolomics) analysis of kidney tissues at distinct IRI time points (2 h, 6 h, 24 h and 7 d). Given that PDK4 was identified as the most consistently upregulated kinase in carbon metabolism, we further explored its effect and mechanism by generating PDK4-knockout mice and employing pharmacological inhibitors. (Results) Our study revealed remarkable metabolic reprogramming, particularly in carbohydrate metabolism, during kidney IRI. Correspondingly, notable gene and protein regulation was observed. Integrated multi-omics analysis demonstrated that PDK4 activation plays a pivotal role in modulating carbon metabolism. Animal experiments confirmed PDK4 activation and further demonstrated that genetic ablation or pharmacological inhibition of PDK4 attenuated renal injury, reduced tubule cell death, facilitated tubular proliferation and improved renal function. Mechanistically, PDK4 contributed to mitochondrial fragmentation through mediating Drp1 activation and translocation. (Conclusion) The present study delineates the extensive molecular reprogramming in kidney IRI and establishes PDK4 as critical nexus between energy metabolism dysregulation and renal tubular injury and cell death. Our multi-omics approach provides valuable insights for identifying novel therapeutic targets and developing renal protective strategies.