Deletion of decay-accelerating factor in kidney tubular cells mitigates kidney fibrosis in aristolochic acid nephropathy.

Local complement activation is increasingly recognized as a key contributor to kidney injury and fibrosis, although protective roles have also been described. The decay-accelerating factor (DAF, CD55) is a membrane-bound complement regulator that disrupts C3 and C5 convertases and limits complement activation on the cell surface. Although renal tubular epithelial cells (RTECs) are a major source of complement components in the kidney, the role of DAF in tubular injury and repair remains unclear. Here, we investigated the function of DAF in kidney tubules using global and tubule-specific DAF knockout mice in a model of aristolochic acid nephropathy (AAN). Publicly available single-cell and single-nucleus transcriptomic datasets revealed high Cd55 expression in proximal tubules that increased following kidney injury. Consistently, DAF protein expression was upregulated in injured tubules in vivo and in primary RTECs exposed to aristolochic acid in vitro. Conversely, DAF-deficient RTECs exhibited increased surface C3 deposition, indicating enhanced local complement activation. Unexpectedly, global DAF deficiency did not worsen acute kidney injury but resulted in improved renal function and reduced fibrosis 6 wk of AAN. Tubule-specific deletion of DAF reproduced this phenotype, with lower blood urea nitrogen levels, preserved tubular architecture, and reduced expression of fibrosis markers, including fibronectin, α-smooth muscle actin, and kidney injury molecule-1. These findings suggest that injury-induced upregulation of DAF in tubular cells may limit protective complement signaling and promote maladaptive repair. Deletion of DAF in RTECs mitigates fibrosis in AAN, revealing an unexpected cell-specific role of complement regulation in the transition from acute to chronic kidney disease.NEW & NOTEWORTHY The decay-accelerating factor (DAF, CD55) is traditionally viewed as protective by limiting complement activation. Unexpectedly, we show that kidney tubular epithelial cells upregulate DAF after injury and that tubule-specific DAF deletion mitigates fibrosis in aristolochic acid nephropathy. These findings reveal a previously unrecognized, cell type-specific role for complement regulation in the kidney and suggest that enhancing local complement signaling in tubular cells may promote adaptive repair during the transition from acute kidney injury to chronic kidney disease.