Potential role of molecular hydrogen therapy on oxidative stress and redox signaling in chronic kidney disease

Oxidative stress plays a key role in chronic kidney disease (CKD) development and progression, inducing kidney cell damage, inflammation, and fibrosis. However, effective therapeutic interventions to slow down CKD advancement are currently lacking. The multifaceted pharmacological effects of molecular hydrogen (H₂) have made it a promising therapeutic avenue. H₂ is capable of capturing harmful ^•OH and ONOO^- while maintaining the crucial reactive oxygen species (ROS) involved in cellular signaling. The NRF2-KEAP1 system, which manages cell redox balance, could be used to treat CKD. H₂ activates this pathway, fortifying antioxidant defenses and scavenging ROS to counteract oxidative stress. H₂ can improve NRF2 signaling by using the Wnt/β-catenin pathway and indirectly activate NRF2-KEAP1 in mitochondria. Additionally, H₂ modulates NF-κB activity by regulating cellular redox status, inhibiting MAPK pathways, and maintaining Trx levels. Treatment with H₂ also attenuates HIF signaling by neutralizing ROS while indirectly bolstering HIF-1α function. Furthermore, H₂ affects FOXO factors and enhances the activity of antioxidant enzymes. Despite the encouraging results of bench studies, clinical trials are still limited and require further investigation. The focus of this review is on hydrogen's role in treating renal diseases, with a specific focus on oxidative stress and redox signaling regulation, and it discusses its potential clinical applications.