Roxadustat, a HIF-PHD inhibitor with exploitable potential on diabetes-related complications

Abstract

Diabetes mellitus (DM) is a group of metabolic diseases caused by absolute or relative deficiency of insulin secretion and characterized by chronic hyperglycemia. Its complications affect almost every tissue of the body, usually leading to blindness, renal failure, amputation, etc. and in the final stage, it mostly develops into cardiac failure, which is the main reason why diabetes mellitus manifests itself as a high clinical lethality. The pathogenesis of diabetes mellitus and its complications involves various pathological processes including excessive production of mitochondrial reactive oxygen species (ROS) and metabolic imbalance. Hypoxia-inducible Factor (HIF) signaling pathway plays an important role in both of the above processes. Roxadustat is an activator of Hypoxia-inducible Factor-1α, which increases the transcriptional activity of Hypoxia-inducible Factor-1α by inhibiting hypoxia-inducible factor prolyl hydroxylase (HIF-PHD). Roxadustat showed regulatory effects on maintaining metabolic stability in the hypoxic state of the body by activating many downstream signaling pathways such as vascular endothelial growth factor (VEGF), glucose transporter protein-1 (GLUT1), lactate dehydrogenase (LDHA), etc. This review summarizes the current research findings of roxadustat on the diseases of cardiomyopathy, nephropathy, retinal damage and impaired wound healing, which also occur at different stages of diabetes and greatly contribute to the damage caused by diabetes to the organism. We attempts to uncover a more comprehensive picture of the therapeutic effects of roxadustat, and inform its expanding research about diabetic complications treatment.

Keywords: diabetes mellitus; diabetic cardiomyopathy (DCM); diabetic nephropathy; hypoxia-inducible factor; roxadustat.

FIGURE 1

Roxadustat, a potential therapeutic drug for diabetes-related complications treatment. The pathogenesis of diabetes-related complications is related to the HIF-1α-mediated metabolic imbalance. As an inhibitor of HIF-PHD, roxadustst shows potentially therapeutic effects on diabetic complications.