FcRn Upregulation Exacerbates Podocyte Injury via Insulin Resistance-Induced Autophagy Disorder in Diabetic Kidney Disease.

Abstract

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.