Targeting a Novel AREG+ Dendritic Cell Alleviates Renal Fibrosis Induced by Ischemia-Reperfusion Injury.

Renal ischemia-reperfusion injury (RIRI) is a major cause of acute tubular damage and a key driver of maladaptive repair and fibrosis. However, the cellular initiators that connect early immune activation to tubular epithelial-mesenchymal transition (EMT) during RIRI remain poorly defined. Here, we established a human RIRI model by modifying the surgical procedures in patients undergoing radical nephrectomy and confirmed successful injury induction by tubular dilation, severe mitochondrial swelling and increased apoptosis in renal tissues. Using single-cell RNA sequencing, we uncovered an underappreciated dendritic cell (DC) subset, CD11c+AREG+ DCs, that expands after RIRI, coinciding with EMT activation in tubular epithelial cells at early stages. Notably, ligand-receptor inference revealed markedly enhanced communication between CD11c+AREG+ DCs and tubular epithelial cells after RIRI, suggesting the AREG-EGFR as a dominant axis. Mechanistically, CD11c+AREG+ DCs initiate and promote tubular EMT via AREG-dependent EGFR signalling, establishing a direct causal link between this DC population and injured tubular epithelial cells. Importantly, Areg knockdown or DC depletion significantly alleviated tubular damage and fibrosis and preserved kidney function in the IRI mouse model, which highlights these cells could be potential therapeutic targets for mitigating RIRI.