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

Summary

Using in vivo LPS-induced S-AKI and HK-2 cell models, the authors identify GATM as a downregulated proximal tubule gene whose overexpression restores mitochondrial energetics and reduces injury. Mechanistically, GATM suppresses PDK4-driven aerobic glycolysis, lowers lactate, increases ATP, and its protection is abrogated by PDK4 overexpression.

Key Findings

• GATM is downregulated in S-AKI across four GEO datasets and LPS models.
• AAV-mediated GATM overexpression improves renal function, reduces tubular injury markers (KIM-1, IL-6, Caspase-3, 4-HNE), and mitigates mitochondrial damage.
• GATM suppresses PDK4 and glycolytic effectors (p-PDHA, HK2, LDHA, GLUT1), lowering lactate and increasing ATP; PDK4 overexpression abolishes GATM’s protection.

Clinical Implications

Therapeutically modulating the GATM–PDK4 pathway could preserve tubular energetics in S-AKI. The pathway suggests biomarker candidates (PDK4, glycolytic enzymes, lactate) for monitoring renal metabolic stress in sepsis.

Limitations

• LPS-induced S-AKI may not fully capture polymicrobial or clinically heterogeneous sepsis
• Human validation beyond HK-2 cells is limited; no pharmacologic targeting of GATM/PDK4 tested

Future Directions

Validate GATM–PDK4 signaling in human S-AKI biopsies and test pharmacologic modulators or gene therapies in clinically relevant sepsis models; evaluate translational biomarkers for patient stratification.