Phosphoglycerate kinase 1 contributes to diabetic kidney disease through enzyme-dependent and independent manners.
Summary
This mechanistic study identifies PGK1 as a central driver of DKD via dual modes: enzymatic 3-PG–GPX1–NLRP3 activation and non-enzymatic Aldh1l1–UNC5CL inflammation. Genetic manipulation in renal tubules and small-molecule antagonists (including an FDA-approved drug) ameliorated DKD in models, nominating PGK1 as a druggable target.
Key Findings
- PGK1 is upregulated in DKD patients and mice; tubular PGK1 knockout mitigates DKD, while overexpression worsens it.
- Enzymatic 3-PG production inhibits GPX1, activating NLRP3 inflammasome; non-enzymatic PGK1 binds Aldh1l1 to promote UNC5CL-mediated inflammation.
- PAX5 drives PGK1 upregulation in DKD; small-molecule antagonists (C-16, lirinidine, oxantel pamoate) prevent DKD in models.
Clinical Implications
PGK1 inhibition could complement current DKD therapies by targeting tubular metabolic–inflammasome pathways. Repurposing oxantel pamoate warrants early-phase clinical testing with biomarkers (3-PG, inflammasome readouts).
Why It Matters
It uncovers a novel, targetable metabolic–inflammatory axis in DKD and provides immediate translational leads (three antagonists) that prevented DKD in vivo.
Limitations
- Preclinical study; no human interventional data
- Potential off-target effects and long-term safety of antagonists remain unknown
Future Directions
Phase 1/2 trials of oxantel pamoate with tubular injury and inflammasome biomarkers; medicinal chemistry to optimize PGK1-selective antagonists; patient stratification by PGK1/PAX5/3-PG signatures.
Study Information
- Study Type
- Basic/Mechanistic
- Research Domain
- Pathophysiology/Treatment
- Evidence Level
- V - Preclinical mechanistic evidence from animal and cellular models with pharmacologic validation
- Study Design
- OTHER