Aryl Hydrocarbon Receptor Pathway Augments Peritoneal Fibrosis in a Murine CKD Model Exposed to Peritoneal Dialysate.

Abstract

Background: Chronic kidney disease (CKD) is a pro-inflammatory and pro-fibrotic condition and can independently alter the peritoneal membrane structure. Peritoneal dialysis (PD) results in profound alterations in the peritoneal membrane. The mechanisms contributing to the alterations of the peritoneal membrane structure in CKD milieu, along with peritoneal dialysis, are poorly understood.

Methods: Here, we show that human 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 the AHR activity in endothelial cells of peritoneal microvasculature in CKD mice.

Results: Treatment of CKD mice with an AHR inhibitor in peritoneal dialysate for two weeks resulted in a 7-fold reduction in AHR expression in the endothelial cells of sub-peritoneal capillaries, a 5-fold decrease in subperitoneal space, and a 9-fold decrease in fibrosis and collagen deposition compared to vehicle-treated CKD mice. AHR inhibition reduced inflammation, subperitoneal neovascular areas, and its downstream target, tissue factor. The AHR inhibitor treatment normalized the peritoneal dialysate-induced pro-inflammatory and profibrotic cytokines, such as IL-6, MCP1, and MIP1 levels, in CKD mice.

Conclusions: This study uncovers the activation of the AHR-cytokine axis in the endothelial cells of subperitoneal vessels in humans and mice with CKD, which is likely to prime the peritoneal membrane to peritoneal dialysate-mediated 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.