Abstract: TH-PO256
Network Collagen VIII Increases Fibrotic Remodeling and Risk of Arteriovenous Fistula Maturation Failure
Session Information
- Vascular Access: From Biology to Managing Complications
November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Dialysis
- 703 Dialysis: Vascular Access
Authors
- Vazquez-Padron, Roberto I., University of Miami School of Medicine, Miami, Florida, United States
- Rojas, Miguel G., University of Miami School of Medicine, Miami, Florida, United States
- Tabbara, Marwan, University of Miami School of Medicine, Miami, Florida, United States
- Pereira-Simon, Simone, University of Miami School of Medicine, Miami, Florida, United States
- Santos, Nieves, University of Miami School of Medicine, Miami, Florida, United States
- Rauf, Mohd Ahmar, University of Miami School of Medicine, Miami, Florida, United States
- Challa, Akshara Sree, University of Miami School of Medicine, Miami, Florida, United States
- Duque, Juan Camilo, University of Miami School of Medicine, Miami, Florida, United States
- Martinez, Laisel, University of Miami School of Medicine, Miami, Florida, United States
Background
Excessive postoperative fibrosis is associated with maturation failure of arteriovenous fistulas (AVF). Therefore, targeted therapies that modulate extracellular matrix (ECM) deposition may represent a plausible strategy to improve maturation outcomes.
Methods
Transcriptome-wide changes during the vein to AVF transformation were studied in 38 stage 5 chronic kidney disease patients undergoing surgeries for two-stage AVF creation (19 matured, 19 failed) using whole-genome RNA sequencing. Pairwise bioinformatic analyses followed by validation experiments were used to identify changes during postoperative ECM remodeling in association with maturation failure.
Results
A total of 3,637 transcripts were differentially expressed (DEG) between veins and AVFs independent of maturation outcome, with >87% upregulated after AVF creation. Over 250 core ECM and ECM-affiliated genes stood out in terms of expression levels and magnitude of fold change, including fibrillar collagens I and III, basement collagens IV and VIII, and multiplexin collagen XVIII. We identified 102 DEGs in association with AVF failure, only eight of which were upregulated in AVFs that failed and which included COL8A1. Upregulation of collagen VIII in AVFs that failed was validated by immunohistochemistry. In vitro experiments with primary smooth muscle cells (SMC) from basilic veins confirmed that the canonical TGFb-Smad2/3 pathway was primarily responsible for COL8A1 expression. Importantly, inhibition of COL8A1 by siRNA modulated the SMC response to TGFb signaling and decreased the expression of fibronectin and fibrillar COL1A1 in response to TGFb stimulation.
Conclusion
This work supports an important role for collagen VIII in fibrotic remodeling and failure of newly created AVF.
Funding
- NIDDK Support