Abstract: TH-PO0223
Spatially Restricted C3-LRP1 Axis Links Tubular Injury to Kidney Fibrosis
Session Information
- CKD: Mechanisms of Injury and Fibrosis - 1
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Sabapathy, Vikram, University of Virginia, Charlottesville, Virginia, United States
- Chauss, Daniel, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Zheng, Shuqiu, University of Virginia, Charlottesville, Virginia, United States
- Trujillo-Ochoa, Jorge Luis, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Melo Ferreira, Ricardo, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Raju, Resmi, Massachusetts General Hospital, Boston, Massachusetts, United States
- Freiwald, Tilo, Hamburg Center for Kidney Health, Hamburg, Germany
- Migliorini, Mary, University of Maryland Baltimore School of Medicine, Baltimore, Maryland, United States
- Sharma, Rahul, University of Virginia, Charlottesville, Virginia, United States
- Okusa, Mark D., University of Virginia, Charlottesville, Virginia, United States
- Jain, Sanjay, Washington University in St Louis School of Medicine, St. Louis, Missouri, United States
- Eadon, Michael T., Indiana University School of Medicine, Indianapolis, Indiana, United States
- Strickland, Dudley, University of Maryland Baltimore School of Medicine, Baltimore, Maryland, United States
- Afzali, Behdad, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Portilla, Didier, University of Virginia, Charlottesville, Virginia, United States
Background
Local complement activation is implicated in the transition from acute kidney injury (AKI) to chronic kidney disease (CKD), but the spatial niches and cellular interactions through which complement promotes fibrosis remain incompletely defined. We hypothesized that spatial profiling of intact injured kidneys would nominate specific microenvironments in which the processes of AKI to CKD are especially prominent. We used spatial transcriptomics to map complement-associated injury programs while preserving kidney architecture.
Methods
Formalin-fixed paraffin-embedded kidney sections from mouse ischemia-reperfusion injury (IRI), unilateral ureteral obstruction (UUO), and sham controls were profiled using 10x Visium HD and Xenium. Clustering, differential gene expression, spatial proximity mapping, trajectory analysis, and Bin2Cell segmentation were used to define cell states and spatial relationships. Key findings were validated by RNAscope, flow cytometry, co-immunoprecipitation, confocal imaging, and surface plasmon resonance (SPR).
Results
IRI and UUO kidneys showed loss of healthy proximal tubules, expansion of injured proximal tubule states, immune-cell infiltration, and stromal activation. A prominent complement gene signature was present in injured kidneys compared with sham controls and was especially enriched in expanded spatial niches containing injured tubules, macrophages, and activated stromal cells. Ligand-receptor analysis nominated C3-LRP1 as a leading complement-associated interaction at these sites, with C3 expressed by Havcr1- and Vcam1-positive injured proximal tubules and Lrp1 expressed by macrophages. RNAscope and confocal imaging confirmed spatial juxtaposition of these populations. SPR demonstrated direct binding between C3-derived fragments and LRP1, supporting a candidate ligand-receptor interaction. Increased C3 and LRP1 expression was also observed in kidney biopsies from patients with AKI and CKD in the Kidney Precision Medicine Project cohort.
Conclusion
These findings identify a spatially organized C3-LRP1 axis linking injured proximal tubules to fibro-immune niches after kidney injury. This pathway provides a candidate mechanism by which local complement activation may amplify tissue remodeling and highlights LRP1-associated signaling as a potential therapeutic target in kidney fibrosis.
Funding
- NIDDK Support