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

Andrea Tóth; Dávid Máté Csiki; Béla Nagy Jr; Enikő Balogh; Gréta Lente; Haneen Ababneh; Árpád Szöőr; Viktória Jeney

doi:10.3389/fphar.2022.798053

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

Front Pharmacol. 2022 Feb 7:13:798053. doi: 10.3389/fphar.2022.798053. eCollection 2022.

Authors

Andrea Tóth^{1

2}, Dávid Máté Csiki^{1

2}, Béla Nagy Jr³, Enikő Balogh¹, Gréta Lente^{1

2}, Haneen Ababneh^{1

2}, Árpád Szöőr⁴, Viktória Jeney¹

Affiliations

¹ MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
² Doctoral School of Molecular Cell and Immune Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
³ Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
⁴ Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

Abstract

Aims: 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 via 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. Methods and Results: 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. Conclusion: 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.

Keywords: anemia; chronic kidney disease (CKD); daprodustat; hypoxia-inducible factor-1; prolyl hydroxylase inhibitor (PHI); vascular calcification; vascular smooth muscle cell.