Febuxostat facilitates neovasculogenesis in chronic kidney disease through xanthine oxidase/NADPH oxidase/c-Jun signaling pathways

The accumulation of uremic toxins in circulation contributes to the cardiovascular diseases that result from chronic kidney disease (CKD). Indoxyl sulfate (IS), which is a protein-bound uremic toxin, promotes cardiovascular diseases with impaired neovascularization by increasing the reactive oxygen species (ROS). This study aimed to investigate febuxostat, a potent xanthine oxidase (XO) inhibitor, for its potential effects on the mechanisms of neovasculogenesis in CKD. CKD mice were generated by 5/6 subtotal nephrectomy and orally administered with febuxostat. Human aortic endothelial cells (HAECs) were used and treated with IS to simulate the CKD conditions in vitro. In the CKD mice, febuxostat reduced systemic ROS and preserved kidney function, as evidenced by the reduced levels of serum blood urea nitrogen, creatinine, urinary albumin-to-creatinine ratios, and renal inflammatory proteins. Furthermore, febuxostat improved neovasculogenesis in an aortic ring assay, a Matrigel plug assay, and a wound healing assay, as evidenced by increased microvascular sprouting in the aortic rings, hemoglobin contents, and capillary density in the CKD mice. In IS-stimulated HAECs, the antioxidative, pro-angiogenic, and anti-inflammatory effects of febuxostat enhanced the tube formation and migration abilities via the XO/p47/c-Jun signaling pathways. In summary, febuxostat might provide renal protection and facilitate neovasculogenesis in CKD. Further clinical study may need to be conducted to verify the effects of febuxostat in CKD patients with vascular complications.