Transient tubular membrane injury is converted into persistent fibrosis through a macrophage–fibroblast relay
Year: 2026
Type: preprint
Abstract: A central unresolved problem in acute kidney injury (AKI) is how a transient epithelial insult is converted into persistent fibrotic repair that drives progression toward chronic kidney disease. Although tubular, immune and stromal responses are individually well recognized, the mechanistically continuous relay linking these three compartments has remained unresolved. Here we define a directional information-conversion pathway spanning injured tubular epithelial cells, macrophages and fibroblasts. Time-resolved single-cell profiling identified a TREM2/SPP1 macrophage state that emerged as post-ischemic repair became fibrotic. Tubular injury remodeled phosphatidylserine (PS) species, increased oxidized PS and PS externalization, and generated a membrane-lipid context for TREM2 sensing, supported by PS masking, defined liposomes and orthogonal binding assays. Structure–function analysis separated R47-dependent phospholipid recognition from K183-dependent DAP12 coupling, linking membrane damage to SYK activation and NF-κB/AP-1–driven Spp1 transcription. Macrophage-derived SPP1 then activated ITGAV/ITGB1-associated FAK–SMAD2/3 signaling, fibroblast contraction and matrix production. Crucially, repair-phase SPP1 neutralization and post-injury Cx3cr1-lineage Trem2 deletion attenuated fibrosis, with delayed Trem2 deletion protective in both ischemic and obstructive injury. Human single-cell, spatial, urinary and tissue analyses showed cross-species and cross-scale convergence. These findings resolve how transient tubular membrane damage is successively transformed across three cellular compartments into persistent, yet interruptible, fibrotic repair.
Authors: Peihan Wang, Yuan Ruan, Ting Rao, Bojun Li, Fan Cheng, Wei Li
Institutions: Wuhan University, Renmin Hospital of Wuhan University
Language: English
Topic: Acute Kidney Injury Research
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1102584726, G8005219297
OpenAlex ID: W7219722875