Abstract: TH-PO213
Activation of Aryl Hydrocarbon Receptor by an Indolic Uremic Toxin Increases the Risk of Deep Venous Thrombosis
Session Information
- Hypertension and CVD: Basic Research Findings
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1601 Hypertension and CVD: Basic
Authors
- Pina Beltran, Blanca, Aix-Marseille Universite, Marseille, Provence-Alpes-Côte d'Azu, France
- Roffino, Sandrine, Aix-Marseille Universite, Marseille, Provence-Alpes-Côte d'Azu, France
- Mc kay, Nathalie, Aix-Marseille Universite, Marseille, Provence-Alpes-Côte d'Azu, France
- Poitevin, Stéphane, Aix-Marseille Universite, Marseille, Provence-Alpes-Côte d'Azu, France
- Burtey, Stephane, Aix-Marseille Universite, Marseille, France
Background
During chronic kidney disease (CKD), the accumulation of indolic uremic toxins, such as indoxyl sulfate (IS), occurs. Activation of the aryl hydrocarbon receptor (AHR), their receptor, leads to increased tissue factor expression, resulting in a prothrombotic state. Our goal is to explore if the activation of AHR could explain the risk of deep venous thrombosis (DVT) during CKD.
Methods
We induced DVT in mice by partially ligating the inferior vena cava (IVC) (Figure 1A). To investigate the role of AHR and uremic toxins, we administered IS or its control (KCl) to 9-week-old normorenal wild-type or Ahr-/- mice for 4 days prior to the IVC ligation procedure, immediately after, and 8h post-procedure. Mice were sacrificed 24h after ligation. The primary evaluation criterion was the presence of a thrombus. TAT and IS were dosed and gene expression of IS/AHR related genes at the liver level determined.
Results
Injection of IS led to increased thrombus presence (58% in IS-injected mice vs. 24% in control) without a sex-related impact. The absence of AHR significantly reduced thrombotic risk (11% in IS-injected Ahr-/- mice vs. 25% in control) (Figure 1B). IS appeared to increase thrombus size and weight compared to control (Figure 1C). The effect of IS is believed to be local (at the ligature site, where the blood flow is diminished), since mice showed no differences in their hypercoagulable state (similar TAT levels). Preliminary results revealed a fibrin sponge-like structure in regions with abundant red blood cells, while platelet-rich areas exhibited a more compact structure, with a higher concentration of white blood cells (Figure 2). There may also be differences in thrombus composition among the different groups.
Conclusion
Accumulation of IS and activation of AHR are associated with an increased number of thrombotic events in our murine DVT model. This likely explains the heightened risk of venous thromboembolism observed in CKD, as well as during exposure to AHR agonists such as certain pesticides or tobacco smoking.