GATM alleviates sepsis-induced acute kidney injury via PDK4-mediated glycolytic reprogramming in renal tubular epithelial cells.

Summary

Cross-dataset discovery and preclinical validation identify GATM as a protective regulator in S-AKI. GATM overexpression suppresses PDK4-driven glycolysis, lowers lactate, boosts ATP, and mitigates tubular and mitochondrial injury; PDK4 overexpression reverses these benefits, positioning the GATM–PDK4 axis as a targetable metabolic pathway.

Key Findings

• GATM was identified across four GEO datasets as a key downregulated gene in proximal tubule cells during S-AKI and LPS-stimulated HK-2 cells.
• AAV-mediated GATM overexpression improved renal function, reduced KIM-1, IL-6, Caspase-3, and 4-HNE, and mitigated mitochondrial injury in LPS-induced S-AKI mice.
• GATM overexpression downregulated PDK4, decreased glycolytic markers (p-PDHA, HK2, LDHA, GLUT1) and lactate, and increased ATP in HK-2 cells.
• PDK4 overexpression abolished GATM’s protective effects, enhancing glycolysis, raising lactate, and reducing ATP, supporting a GATM→PDK4 pathway.

Clinical Implications

While preclinical, the GATM–PDK4 axis suggests therapeutic avenues such as PDK4 inhibition or GATM augmentation to prevent or treat sepsis-associated AKI by restoring mitochondrial function.

Limitations

• LPS-induced S-AKI may not fully recapitulate polymicrobial sepsis
• Overexpression models without complementary loss-of-function of GATM in vivo
• Translational biomarkers and dosing strategies for PDK4/GATM modulation not evaluated

Future Directions

Validate GATM loss-of-function in diverse sepsis models (e.g., CLP), test PDK4 inhibitors as therapeutics, and develop translatable biomarker panels for patient stratification in S-AKI.