Diabetic kidney disease (DKD) remains the leading cause of end-stage renal disease worldwide, despite therapeutic advances. Podocyte injury constitutes a critical pathogenic process in DKD. This study elucidated the role of the neonatal Fc receptor (FcRn) in DKD-associated podocyte injury. In DKD, glomerular FcRn expression was markedly elevated and inversely correlated with podocin levels. In diabetic mice, podocyte-specific FcRn deficiency significantly ameliorated insulin resistance and mitigated podocyte damage. Mechanistically, FcRn upregulation in diabetic podocytes exacerbated insulin resistance, suppressed AKT/mTOR signaling, and impaired autophagy, thereby promoting podocyte injury. These findings identify FcRn as a pivotal contributor to podocyte injury in DKD and suggest that FcRn targeting represents a promising therapeutic strategy.
- Neonatal Fc receptor (FcRn) mediates podocyte injury in immune complex nephropathies, but its role in diabetic kidney disease (DKD) remains undefined.
- This study demonstrates marked FcRn upregulation in DKD podocytes and elucidates the functional consequences of podocyte FcRn deficiency.
- FcRn deficiency protects podocytes in DKD by restoring autophagy via enhanced insulin sensitivity and subsequent AKT/mTOR signaling activation.
- These findings identify FcRn as a novel therapeutic target for DKD, offering a strategy to mitigate the substantial residual risk of disease progression despite current therapies.
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