Daprodustat Accelerates High Phosphate-Induced Calcification Through the Activation of HIF-1 Signaling

Area of Science:

• Nephrology
• Cardiovascular Biology
• Pharmacology

Background:

• Anemia is a common complication of chronic kidney disease (CKD).
• Daprodustat (DPD) is a novel drug that stimulates red blood cell production by activating the hypoxia-inducible factor 1 (HIF-1) pathway.
• HIF-1 activation has been linked to vascular calcification.

Purpose of the Study:

• To investigate the impact of Daprodustat (DPD) on high phosphate-induced vascular calcification.
• To explore the role of the HIF-1 pathway in DPD-mediated calcification.

Main Methods:

• Experiments were conducted using human aortic vascular smooth muscle cells (VSMCs), mouse aorta rings, and a murine model of CKD induced by adenine and high phosphate.
• DPD's effect on HIF-1α and HIF-2α stabilization and HIF-1 pathway activation was assessed.
• Calcification was evaluated using osteosense staining and by measuring calcification in VSMCs and aorta rings.

Main Results:

• DPD stabilized HIF-1α and HIF-2α, activating the HIF-1 pathway in VSMCs.
• DPD treatment enhanced phosphate-induced calcification in cultured VSMCs and mouse aorta rings.
• In CKD mice, DPD corrected anemia but exacerbated aortic calcification.
• Inhibiting HIF-1 transcriptional activity attenuated DPD's calcification effects.

Conclusions:

• Sustained activation of the HIF-1 pathway by Daprodustat may accelerate medial calcification in CKD patients with hyperphosphatemia.
• Long-term clinical studies are necessary to evaluate this potential risk.