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.
Highlights
Chronic kidney disease (CKD) is an irreversible and progressive disease associated with alteration of the renal structure and decline of kidney functions (Webster et al, 2017)
Because 1) prolyl hydroxylase inhibitor (PHI) target the hypoxiainducible factor (HIF) pathway and 2) hypoxia-mediated activation of hypoxia inducible factor 1 (HIF-1) induces the calcification of vascular smooth muscle cells (VSMCs), here, we investigated the effect of the PHI daprodustat (GSK1278863, DPD) on calcification in both in vitro and in vivo conditions
First, we set up an in vitro model of vascular calcification with cultured human VSMCs maintained in a calcification medium that was supplemented with different concentrations of inorganic phosphate (Pi) (0–2.5 mmol/ L) under normoxic (21% O2) and hypoxic (1% O2) conditions
Summary
Chronic kidney disease (CKD) is an irreversible and progressive disease associated with alteration of the renal structure and decline of kidney functions (Webster et al, 2017). CKD patients have five to ten times higher risk of premature death than the general population, which is largely attributed to death from cardiovascular diseases (Sarnak et al, 2003; Di Angelantonio et al, 2007; Webster et al, 2017). The etiology of CKD-associated anemia is complex with the contribution of reduced production of erythropoietin (EPO), a kidney-derived factor responsible for stimulating erythropoiesis, shortened red blood cell lifespan, and iron deficiency (Babitt and Lin, 2012; Hanna et al, 2021). Red blood cell transfusion remained a treatment option only for blood loss or severe hyporesponsiveness for ESAs (Locatelli et al, 2013)
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