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

Tóth, Andrea and Csiki, Dávid Máté and Nagy, Béla Jr and Balogh, Enikő and Lente, Gréta and Szöőr, Árpád and Jeney, Viktória (2022) Daprodustat Accelerates High Phosphate-Induced Calcification Through the Activation of HIF-1 Signaling. FRONTIERS IN PHARMACOLOGY, 13. No. 798053. ISSN 1663-9812

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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-1 alpha and HIF-2 alpha 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-1 alpha 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.

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