Endothelin type A receptor blockade reduces vascular calcification and inflammation in rats with chronic kidney disease.

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.