Journal
ANTIOXIDANTS
Volume 11, Issue 11, Pages -Publisher
MDPI
DOI: 10.3390/antiox11112183
Keywords
advanced glycation end products; atherosclerosis; diabetic kidney disease; inflammation; methylglyoxal; prolyl hydroxylase domain proteins; reactive oxygen species; sirtuin-1; sodium glucose co-transporter 2 inhibitors; Warburg effect
Funding
- EFSD/Sanofi European Research Programme in Macrovascular Complications of Diabetes
- Sapienza University of Rome
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Oxidative stress and hypoxia-inducible factors (HIFs) play crucial roles in the pathogenesis of diabetic cardiovascular and renal diseases, with reactive oxygen species (ROS) mediating cell signaling and contributing to the development of vascular complications.
Oxidative stress and hypoxia-inducible factors (HIFs) have been implicated in the pathogenesis of diabetic cardiovascular and renal diseases. Reactive oxygen species (ROS) mediate physiological and pathophysiological processes, being involved in the modulation of cell signaling, differentiation, and survival, but also in cyto- and genotoxic damage. As master regulators of glycolytic metabolism and oxygen homeostasis, HIFs have been largely studied for their role in cell survival in hypoxic conditions. However, in addition to hypoxia, other stimuli can regulate HIFs stability and transcriptional activity, even in normoxic conditions. Among these, a regulatory role of ROS and their byproducts on HIFs, particularly the HIF-1 alpha isoform, has received growing attention in recent years. On the other hand, HIF-1 alpha and HIF-2 alpha exert mutually antagonistic effects on oxidative damage. In diabetes, redox-mediated HIF-1 alpha deregulation contributes to the onset and progression of cardiovascular and renal complications, and recent findings suggest that deranged HIF signaling induced by hyperglycemia and other cellular stressors associated with metabolic disorders may cause mitochondrial dysfunction, oxidative stress, and inflammation. Understanding the mechanisms of mutual regulation between HIFs and redox factors and the specific contribution of the two main isoforms of HIF-alpha is fundamental to identify new therapeutic targets for vascular complications of diabetes.
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