Abstract: TH-OR64
Aryl Hydrocarbon Receptor Pathway Enhances Peritoneal Fibrosis in a Murine CKD Model Exposed to Peritoneal Dialysate
Session Information
- Home Dialysis Hodgepodge: Novel Mechanisms, Solutions, Technologies, and Ideas
October 24, 2024 | Location: Room 8, Convention Center
Abstract Time: 04:30 PM - 04:40 PM
Category: Dialysis
- 802 Dialysis: Home Dialysis and Peritoneal Dialysis
Authors
- Yadati, Pranav, Boston University, Boston, Massachusetts, United States
- Lotfollahzadeh, Saran, Boston University, Boston, Massachusetts, United States
- Yin, Wenqing, Boston University, Boston, Massachusetts, United States
- Francis, Jean M., Boston University, Boston, Massachusetts, United States
- Chitalia, Vipul C., Boston University, Boston, Massachusetts, United States
Background
Peritoneal dialysis (PD) results in profound alterations in the peritoneal membrane. Chronic kidney disease (CKD) is a profibrotic condition characterized by the retention of uremic toxins. The mechanisms contributing to the alterations in the peritoneal membrane, specifically due to uremic solutes and peritoneal dialysate remain poorly understood.
Methods
A mouse model of CKD with peritoneal dialysis was employed along with the molecular and imaging technique for mechanistic probing.
Results
We show in humans that CKD induces peritoneal membrane thickening, fibrosis, and collagen deposition and activates the Aryl Hydrocarbon Receptor pathway (AHR) in the subperitoneal vasculature. Leveraging a novel model of peritoneal dialysis in CKD mice, we confirm these CKD-induced changes in the peritoneal membrane, which are exacerbated upon exposure to the peritoneal dialysate. Peritoneal dialysate further augmented AHR activity in the endothelial cells of peritoneal microvasculature beyond CKD. Treatment of CKD mice with an AHR inhibitor in peritoneal dialysate resulted in a 5-fold decrease in subperitoneal space, a 9-fold decrease in fibrosis (see attached figure) and collagen deposition compared to vehicle-treated CKD mice. AHR inhibition reduced inflammation, subperitoneal neovascular areas, and its downstream target, tissue factor. An AHR inhibitor normalized pro-inflammatory and profibrotic cytokines, such as IL-6, MCP1, and MIP1 levels, in the peritoneal dialysate of CKD mice.
Conclusion
This study, for the first time, demonstrates the AHR activation in the endothelial cells of subperitoneal vessels in human CKD and mice, which is likely to prime the peritoneal membrane to dialysate-induced alterations. This study supports further exploration of AHR as a potential therapeutic target to preserve the structural and functional integrity of the peritoneal membrane in peritoneal dialysis.
Funding
- Private Foundation Support