Role of prolyl hydroxylase/HIF-1 signaling in vascular calcification

Morbidity and mortality of chronic kidney disease (CKD) patients are largely associated with vascular calcification, an actively regulated process in which vascular smooth muscle cells (VSMCs) change into cells similar to osteocytes/chondrocytes, known as trans-differentiation. Cellular and systemic response to low oxygen (hypoxia) is regulated by the prolyl hydroxylase/hypoxia-inducible factor (HIF)-1 pathway. Recent studies highlighted that hypoxia-mediated activation of HIF-1 induces trans-differentiation of VSMCs into bone-forming type through an increase in osteo-/chondrogenic genes. Inhibition of the HIF-1 pathway abolished osteochondrogenic differentiation of VSMCs. Hypoxia strongly enhanced elevated phosphate-induced VSMC osteogenic trans-differentiation and calcification. HIF-1 was shown to be essential for phosphate enhanced VSMC calcification. O-2-dependent degradation HIF-1 is triggered by the prolyl hydroxylase domain proteins (PHD). Prolyl hydroxylase inhibitors, daprodustat and roxadustat, increase high phosphate-induced VC in VSMCs, stabilizing HIF-1 alpha and activating the HIF-1 pathway in these cells. Whether the use of these PHD inhibitors to treat anemia in CKD patients will favor the development and progression of vascular calcification remains to be explored.

Automated summary

The morbidity and mortality of chronic kidney disease (CKD) patients are closely related to vascular calcification. Recent studies have shown that under low oxygen conditions, hypoxia can activate the HIF-1 pathway, causing vascular smooth muscle cells (VSMCs) to transform into bone-forming cells, leading to vascular calcification. Inhibition of the HIF-1 pathway can prevent this differentiation. The combination of phosphate and hypoxia further enhances VSMC calcification. The use of prolyl hydroxylase inhibitors to treat anemia in CKD patients and its effect on vascular calcification needs further exploration.