Abstract: TH-PO1132
Fibroblast Activation Protein (FAP) Modulates Fibrotic Changes and Potential Stromal-Epithelial Cell Interactions in CKD
Session Information
- CKD: Mechanisms, AKI, and Beyond - 1
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Hibbard, Lainey M., Indiana University School of Medicine, Indianapolis, Indiana, United States
- Liu, Sheng, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Jennings, Kayleigh Nicole, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Sulaiman, Xierzhatijiang, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Preciado Lopez, Magdalena, Calico Labs, South San Francisco, California, United States
- Wan, Jun, Indiana University School of Medicine, Indianapolis, Indiana, United States
- White, Kenneth E., Indiana University School of Medicine, Indianapolis, Indiana, United States
Background
Renal fibrosis is the common pathology of most etiologies of chronic kidney disease (CKD); yet there is a need for new fibrotic targets and anti-fibrotic therapeutics for patients with CKD. Fibroblast activation protein (FAP) is a serine protease expressed by activated fibroblasts and is upregulated in fibrosis, but the role of FAP in CKD progression is understudied. Herein, we characterized and tested FAP in a mouse model of CKD.
Methods
Male mice were placed on 0.2% adenine or casein control diet for 2, 4, 6 weeks (w) to induce CKD. Female FAP knockout (KO) and WT littermates were also put on 0.2% adenine or casein diet for 2, 4 w. Visium spatial transcriptomics (ST), scRNAseq, and bulk RNAseq on FAPKO and WT kidneys was performed.
Results
WT CKD mice demonstrated an increase in kidney Fap mRNA with time. Further, increased Fap mRNA was confirmed via ST on kidneys from mice at 4 w on adenine diet (1.24 log2FC). In the same kidneys, CKD mice showed increased FAP immunofluorescence vs. control mice, which colocalized with fibrotic lesions. We next tested expression of genes in FAP+ and FAP- fibroblasts in our scRNAseq dataset from 4 w WT male adenine-CKD kidneys. In addition to known fibroblast markers found in both cell populations (Fn1, Palld, Pdgfrb), we found higher expression of cell-cell interaction/migration and extracellular matrix (ECM) genes in FAP+ fibroblasts, suggesting FAP may enhance kidney fibrosis via altering ECM composition and cell-cell interactions. FAPKO mice with CKD lost less weight and had decreased BUN compared to WT mice, indicating slower CKD progression. The chemokine Cxcl1 was elevated in CKD, with expression localized to the proximal tubules, as determined by ST and confirmed in human CKD samples. Interestingly, FAPKO mice with CKD had decreased renal expression of Cxcl1 at 4 w adenine vs. WT mice. Cxcl1 has been shown to promote cell migration, thus decreased expression with deletion of FAP may affect cell migration in CKD. Additionally, expression of Il1b, an activator of Cxcl1, was decreased in KO mice compared to WT.
Conclusion
FAP is elevated in CKD and may play a role in cell migration and ECM remodeling, potentially through Cxcl1. Further, loss of FAP results in slower CKD progression in the adenine mouse model.
Funding
- NIDDK Support – Calico Labs