Expression and Mechanistic Insights into PDK4 in Hypertensive Renal Damage

Abstract Background and Objective: Hypertensive renal damage (HRD) currently lacks effective early biomarkers and intervention targets. Pyruvate dehydrogenase kinase isozyme 4 (PDK4) plays well‑defined roles in various diseases, but its mechanism in HRD has not been systematically elucidated. This study aimed to explore the role of PDK4—a key molecule that has not been fully studied—in HRD by integrating bioinformatics analysis and experimental validation. Methods: ① Bioinformatics analysis was performed based on the GEO database (GSE37455) to screen differentially expressed genes and conduct functional enrichment analysis. ② Clinical serum samples from HRD patients were collected, and PDK4 levels were measured by ELISA to analyze their correlation with renal function indicators and diagnostic performance. ③ An injury model was established by stimulating human renal tubular epithelial cells (HK‑2) with Ang II, and PDK4 expression was detected. PDK4 was knocked down using lentivirus to evaluate its effects on oxidative stress (ROS) and epithelial‑mesenchymal transition (EMT). ④ RNA‑seq was performed on PDK4‑knockdown cells, and downstream signaling pathways were analyzed by enrichment analysis. Results: ① Bioinformatics analysis indicated that PDK4 is highly expressed in HRD, and related differentially expressed genes were enriched in pathways such as inflammation and apoptosis. ② Clinical samples showed that serum PDK4 expression was highest in the HRD group, negatively correlated with eGFR, and positively correlated with creatinine, urinary protein, etc. The ROC curve revealed an AUC of 0.982 for PDK4 in diagnosing HRD. ③ In cell experiments, Ang II induced upregulation of PDK4 expression, and its knockdown alleviated oxidative stress and EMT progression. ④ RNA‑seq analysis demonstrated that PDK4 knockdown affects pathways including inflammation, oxidative stress, and Wnt. Conclusion: PDK4 is highly expressed in HRD and promotes renal injury by regulating oxidative stress and fibrotic processes, suggesting its value as a potential biomarker and therapeutic target for HRD. This study provides the first systematic evidence of the high expression of PDK4 in HRD and its injury‑promoting mechanism, indicating that PDK4 may serve as a potential novel biomarker and therapeutic target.