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Endothelin type A receptor blockade reduces vascular calcification and inflammation in rats with chronic kidney
Richard Larivière1, Alexandra Gauthier-Bastien, Roth-Visal Ung
1aCHU de Québec - Université Laval Research Center, L'Hôtel-Dieu de Québec HospitalbDépartement de médecine, Faculty of Medicine, Université LavalcDépartement de biologie moléculaire, de biochimie médicale et de pathologie, Faculty of Medicine, Université Laval, Quebec City, Québec, Canada.
Insights
Blocking the endothelin type A (ETA) receptor reduces vascular inflammation and calcification in chronic kidney disease (CKD) rats. This suggests the endothelin system is a therapeutic target for improving cardiovascular health in CKD patients.
Area of Science:
- Cardiovascular Research
- Nephrology
- Pharmacology
Background:
- Arterial stiffness and calcification are significant cardiovascular risk factors in chronic kidney disease (CKD).
- Medial vascular calcification in CKD is linked to inflammation and increased endothelin-1 (ET-1) production.
- The endothelin type A (ETA) receptor is implicated in mediating these detrimental effects.
Purpose of the Study:
- To investigate the role of ET-1, via the ETA receptor, in inducing vascular inflammation, calcification, and stiffness in a rat model of CKD.
- To evaluate the therapeutic potential of ETA receptor blockade in mitigating these CKD-associated vascular complications.
Main Methods:
- Chronic kidney disease (CKD) was induced in Wistar rats via renal mass ablation.
- Medial vascular calcification was induced using a calcium-rich/phosphate-rich diet and vitamin D supplementation.
- Rats received the ETA receptor antagonist atrasentan, and hemodynamic parameters, vascular calcification, smooth muscle cell differentiation, and inflammatory markers were assessed.
Main Results:
- CKD rats with mineral imbalance exhibited increased vascular calcification, blood pressure, and arterial stiffness (pulse wave velocity).
- These changes were accompanied by heightened macrophage infiltration and expression of inflammatory markers and osteoblastic markers.
- Atrasentan treatment significantly reduced vascular calcification, blood pressure, arterial stiffness, inflammation, and osteoblastic differentiation.
Conclusions:
- ETA receptor blockade effectively reduced vascular inflammation, smooth muscle cell differentiation, calcification, and stiffness in a CKD rat model.
- These findings highlight a critical role for ET-1 in medial vascular calcification in CKD with mineral imbalance.
- The endothelin system represents a promising therapeutic target for managing cardiovascular morbidity in CKD patients.
Objective:
Arterial stiffness and calcification are nontraditional cardiovascular risk factors in chronic kidney disease (CKD). Using a rat model of CKD with mineral imbalance, medial vascular calcification has been associated with inflammation and increased endothelin-1 (ET-1) production. We therefore hypothesized that ET-1, through the endothelin type A (ETA) receptor, induces vascular inflammation, calcification and stiffness in CKD.
Methods:
CKD was induced in Wistar rats by renal mass ablation. To induce medial vascular calcification, mineral imbalance was established with a identified as calcium-rich/phosphate-rich diet and vitamin D supplementation (Ca/P/VitD). One group of CKD + Ca/P/VitD rats was given the ETA receptor antagonist atrasentan (10 mg/kg/day) for 6 weeks. Hemodynamic parameters including SBP, pulse pressure (PP) and pulse wave velocity (PWV) were determined. Vascular calcification, smooth muscle cells osteoblastic differentiation and expression of inflammatory markers such as inflammatory cytokines and calgranulins S100A8 and S100A9 were assessed in the thoracic aorta.
Results:
As compared with CKD control rats, CKD + Ca/P/VitD rats developed medal vascular calcification that was associated with increased SBP, PP and PWV. These changes were also associated with increased macrophage infiltration and expression of IL-6, calgranulins and osteoblastic markers. Treatment of CKD + Ca/P/VitD rats with atrasentan reduced vascular calcification, SBP, PP and PWV, macrophage infiltration and expression of IL-1β, IL-6, tumor necrosis factor, calgranulins and osteoblastic markers.
Conclusion:
This study shows that ETA receptor blockade reduced vascular inflammation, smooth muscle cells differentiation, calcification and stiffness indicating a pivotal role for ET-1 in medial vascular calcification in this rat remnant kidney model of CKD with mineral imbalance. Therefore, the endothelin system may be a potential therapeutic target for improving cardiovascular morbidity in patients with CKD.
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ETs are synthesized through a complex sequence of enzymatic steps, primarily involving an enzyme referred to as endothelin-converting enzyme...