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

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.

Editorial: Vascular smooth muscle cell fate and vascular remodeling: Mechanisms, therapeutic targets, and drugs, volume I

“…Daprodustat is a medicine employed to increase erythropoiesis via stabilization of HIF1α. Toth et al (2022) demonstrated that Daprodustat increased aortic calcification in a high phosphate-induced chronic kidney disease mice model. Daprodustat could stabilize HIF1α and HIF2α to accelerate medial calcification, suggesting that there is a possible risk that Daprodustat treatment could accelerate medial calcification in CKD patients with hyperphosphatemia.…”

Hypoxia-Inducible Factor–Prolyl Hydroxyl Domain Inhibitors: From Theoretical Superiority to Clinical Noninferiority Compared with Current ESAs?

“…In addition to metabolic aspects, the HIF system is involved in the adaptation to acute and chronic ischemia, atherogenesis, and vascular calcification. However, data from experimental studies are conflicting because they are strongly influenced by the experimental conditions and by the degree of hypoxia of the affected tissues, possibly activating the three HIF and PHD isoforms differently 86 – 89 …”

Phenotypic plasticity of vascular smooth muscle cells in vascular calcification: Role of mitochondria

“…Hypoxia triggers VSMCs calcification and osteogenic differentiation in a HIF-1-dependent and mitochondrial ROSdependent manner (134)(135)(136). As a key effector of hypoxia response, the hypoxia-inducible factor-1α (HIF-1α) can affect the transcription and activity of related metabolic enzymes and regulate the phenotypic transformation of VSMCs.…”