Oxidative stress and endoplasmic reticulum stress in acute kidney injury: mechanistic crosstalk and therapeutic modulation

Acute kidney injury (AKI) is a complex syndrome with multiple causes, associated with high morbidity and mortality rates. Despite advances in intensive care, effective therapeutic strategies for AKI remain limited. In this review, we examine the roles of oxidative stress and endoplasmic reticulum stress (ERS) in the pathogenesis of AKI. Oxidative stress, marked by the excessive production of reactive oxygen species (ROS), can trigger ERS, leading to misfolded protein accumulation and activation of the unfolded protein response (UPR) in an attempt to restore cellular homeostasis. When ERS becomes prolonged or excessive, persistent activation of UPR pathways such as IRE1, PERK and ATF6 induces apoptosis and further worsens kidney injury. In addition to apoptosis, oxidative stress and ERS also regulate autophagy, a cellular stress response. Together, these pathways promote cellular dysfunction and advance AKI progression. We also discuss potential therapies that target oxidative stress and ERS, such as antioxidants and pharmacological agents targeting UPR pathways, which may offer promising approaches to mitigate AKI. A deeper understanding of the interplay between oxidative stress and ERS in AKI is essential for developing effective therapeutic interventions to improve patient outcomes.