Molecular Interactions Between Reactive Oxygen Species and Autophagy in Kidney Disease

Abstract

Reactive oxygen species (ROS) are highly reactive signaling molecules that maintain redox homeostasis in mammalian cells. Dysregulation of redox homeostasis under pathological conditions results in excessive generation of ROS, culminating in oxidative stress and the associated oxidative damage of cellular components. ROS and oxidative stress play a vital role in the pathogenesis of acute kidney injury and chronic kidney disease, and it is well documented that increased oxidative stress in patients enhances the progression of renal diseases. Oxidative stress activates autophagy, which facilitates cellular adaptation and diminishes oxidative damage by degrading and recycling intracellular oxidized and damaged macromolecules and dysfunctional organelles. In this review, we report the current understanding of the molecular regulation of autophagy in response to oxidative stress in general and in the pathogenesis of kidney diseases. We summarize how the molecular interactions between ROS and autophagy involve ROS-mediated activation of autophagy and autophagy-mediated reduction of oxidative stress. In particular, we describe how ROS impact various signaling pathways of autophagy, including mTORC1-ULK1, AMPK-mTORC1-ULK1, and Keap1-Nrf2-p62, as well as selective autophagy including mitophagy and pexophagy. Precise elucidation of the molecular mechanisms of interactions between ROS and autophagy in the pathogenesis of renal diseases may identify novel targets for development of drugs for preventing renal injury.

Clemaichinenoside protects renal tubular epithelial cells from hypoxia/reoxygenation injury in vitro through activating the Nrf2/HO‐1 signalling pathway

“…Nrf2 is a basic region‐leucine zipper (bZip) transcription factor that acts as an efficient and pivotal line of defensive to counteract environmental insults and endogenous stressors . Under normal conditions, the Nrf2 is tightly controlled in cytoplasm by its inhibitory binding protein Kelch‐like ECH‐associated protein 1 (Keap1) . In adaptation to different stress conditions, Nrf2 translocates into the nucleus, in which Nrf2 forms heterodimers with small musculoaponeurotic fibrosarcoma protein (MAF) K, G, and F, and then binds to the antioxidant response element (ARE) and initiates the transcription of many antioxidant and Phase II detoxification enzymes .…”

Critical Role for AMPK in Metabolic Disease-Induced Chronic Kidney Disease

“…Excessive fat also induces constitutive activation of mTORC1 that directly inhibits AMPK activity, suggesting a link between mTOR and AMPK [156,157]. However, AMPK-mediated activation of autophagy protects against renal injury, particularly in AKI [158]. Regarding metabolic disease-related CKD, Yamahara et al demonstrated that obesity significantly suppressed autophagy in PTC of both mice and humans.…”

Role of Nrf2 in Lipopolysaccharide-Induced Acute Kidney Injury: Protection by Human Umbilical Cord Blood Mononuclear Cells

“…Autophagy is an evolutionarily conserved, dynamic process of degradation of intracellular organelles and macromolecules by lysosomal hydrolases [7]. Previous studies suggest that the low level of autophagy is shown when AKI is detected in septic AKI models [43,44].…”