AUTHOR=Tóth Andrea , Csiki Dávid Máté , Nagy Béla , Balogh Enikő , Lente Gréta , Ababneh Haneen , Szöőr Árpád , Jeney Viktória 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.798053

DOI=10.3389/fphar.2022.798053

ISSN=1663-9812

ABSTRACT=<p><bold>Aims:</bold> Chronic kidney disease (CKD) is frequently associated with other chronic diseases including anemia. Daprodustat (DPD) is a prolyl hydroxylase inhibitor, a member of a family of those new generation drugs that increase erythropoiesis <italic>via</italic> activation of the hypoxia-inducible factor 1 (HIF-1) pathway. Previous studies showed that HIF-1 activation is ultimately linked to acceleration of vascular calcification. We aimed to investigate the effect of DPD on high phosphate-induced calcification.</p><p><bold>Methods and Results:</bold> We investigated the effect of DPD on calcification in primary human aortic vascular smooth muscle cells (VSMCs), in mouse aorta rings, and an adenine and high phosphate-induced CKD murine model. DPD stabilized HIF-1α and HIF-2α and activated the HIF-1 pathway in VSMCs. Treatment with DPD increased phosphate-induced calcification in cultured VSMCs and murine aorta rings. Oral administration of DPD to adenine and high phosphate-induced CKD mice corrected anemia but increased aortic calcification as assessed by osteosense staining. The inhibition of the transcriptional activity of HIF-1 by chetomin or silencing of HIF-1α attenuated the effect of DPD on VSMC calcification.</p><p><bold>Conclusion:</bold> Clinical studies with a long follow-up period are needed to evaluate the possible risk of sustained activation of HIF-1 by DPD in accelerating medial calcification in CKD patients with hyperphosphatemia.</p>