179 - Potential procalcifying effect of Daprodustat on vascular smooth muscle cells (ID 1147)
Abstract
Background and Aims
Chronic kidney disease (CKD) is frequently associated with anemia, partially due to the insufficient production of erythropoietin. Currently this condition is treated with recombinant human erythropoietin, however in advanced CKD its application increase the risk of cardiovascular events. This initiated search for new treatment options including drugs that target the hypoxia inducible factor 1 (HIF1) pathway. One candidate is Daprodustat, a prolyl hydroxylase inhibitor which is currently tested in a Phase3 clinical trial for safety and efficacy to treat anemia in CKD patients. Recent studies revealed that hypoxia contributes to vascular calcification via the activation of HIF1 pathway, therefore we addressed the potential pro-calcifying effect of Daprodustat on vascular smooth muscle cells.
Methods
We induced calcification of human aortic smooth muscle cells (HAoSMCs) with inorganic phosphate (Pi, 1.5-2.5 mmol/L) in the presence or absence of Daprodustat (10-1000 nmol/L). Protein expressions of HIF-1α, Glut-1, ALP and VEGF were evaluated by Western blot and ELISA. Extracellular matrix mineralization was assessed by Alizarin red staining and Ca measurement. Quantitative RT-PCR was used to measure mRNA expressions of osteoblast-specific markers Runx2, Sox9 and ALP.
Results
Daprodustat increased HIF-1α, VEGF and Glut-1 protein expressions in a dose-dependent manner. Daprodustat induced mRNA expressions of osteochondrogenic markers Runx2, Sox9 and ALP, and potentiated the effect of Pi on extracellular matrix calcification in HAoSMCs.
Conclusions
We concluded that Daprodustat increase Pi-mediated osteochondrogenic transdifferentiation and extracellular matrix mineralization of HAoSMCs, Further studies are warranted to address whether Daprodustat increases the risk of vascular calcification in CKD patients.
