GABA ameliorates diabetic kidney disease-induced podocyte injury via JAML-FPR2 axis-mediated suppression of macrophage infiltration

In streptozotocin (STZ)-induced DKD mice, GABA administration significantly improved renal function by reducing serum creatinine, urea nitrogen, 24-hour urine protein, attenuated glomerular hypertrophy/mesangial expansion, and suppressed pro-inflammatory cytokine production (TNF-α, IL-1β, iNOS) in renal tissue and serum.

GABA inhibited glomerular macrophage infiltration (CD68⁺ cells) and M1 polarization while mitigating renal apoptosis and podocyte injury by restoring nephrin and podocin. In a high glucose (HG)-stimulated macrophage-podocyte co-culture model, GABA reduced HG-induced podocyte apoptosis in a macrophage ratio-dependent manner by reversing M1 polarization and inflammatory cytokine overproduction. Mechanistically, GABA normalized DKD-elevated JAML expression in renal tissues and podocytes, while JAML overexpression abolished GABA’s renoprotective effects by reactivating inflammation, macrophage recruitment, and podocyte apoptosis.