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

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.

Tryptophan Metabolites Target Transmembrane and Immunoglobulin Domain-Containing 1 Signaling to Augment Renal Tubular Injury.

Chronic kidney disease (CKD) is characterized by the accumulation of uremic toxins and renal tubular damage. Tryptophan-derived uremic toxins [indoxyl sulfate (IS) and kynurenine (Kyn)] are well-characterized tubulotoxins. Emerging evidence suggests that transmembrane and immunoglobulin domain-containing 1 (TMIGD1) protects tubular cells and promotes survival. However, the direct molecular mechanism(s) underlying how these two opposing pathways crosstalk remains unknown. We posited that IS and Kyn mediate tubular toxicity through TMIGD1 and the loss of TMIGD1 augments tubular injury. Results from the current study showed that IS and Kyn suppressed TMIGD1 transcription in tubular cells in a dose-dependent manner. The wild-type CCAAT enhancer-binding protein ß (C/EBPß) enhanced, whereas a dominant-negative C/EBPß suppressed, TMIGD1 promoter activity. IS down-regulated C/EBPß in primary human renal tubular cells. The adenine-induced CKD, unilateral ureteric obstruction, and deoxycorticosterone acetate salt unilateral nephrectomy models showed reduced TMIGD1 expression in the renal tubules, which correlated with C/EBPß expression. C/EBPß levels negatively correlated with the IS and Kyn levels. Inactivation of TMIGD1 in mice significantly lowered acetylated tubulin, decreased tubular cell proliferation, caused severe tubular damage, and worsened renal function. Thus, the current results demonstrate that TMIGD1 protects renal tubular cells from renal injury in different models of CKD and uncovers a novel mechanism of tubulotoxicity of tryptophan-based uremic toxins.

A Retrograde Implantation Approach for Peritoneal Dialysis Catheter Placement in Mice.

Murine models are employed to probe various aspects of peritoneal dialysis (PD), such as peritoneal inflammation and fibrosis. These events drive peritoneal membrane failure in humans, which remains an area of intense investigation due to its profound clinical implications in managing patients with end-stage kidney disease (ESKD). Despite the clinical importance of PD and its related complications, current experimental murine models suffer from key technical challenges that compromise the models' performance. These include PD catheter migration and kinking and usually warrant earlier catheter removal. These limitations also drive the need for a greater number of animals to complete a study. Addressing these drawbacks, this study introduces technical improvements and surgical nuances to prevent commonly observed PD catheter complications in a murine model. Moreover, this modified model is validated by inducing peritoneal inflammation and fibrosis using lipopolysaccharide injections. In essence, this paper describes an improved method to create an experimental model of PD.