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.
Highlights
Reactive oxygen species (ROS) are short-lived oxygen-containing molecules that are generated by enzymatic and non-enzymatic redox reactions during cellular aerobic metabolism [1,2]
In kidneys from a unilateral ureteral obstruction model (UUO) at day 7, FOXO3 activation increased both the mRNA and protein levels of key autophagy proteins including Ulk1, beclin-1, Atg9A, Atg4B, and Bnip3 [172], suggesting that FOXO3 is an important regulator of autophagy in renal tubular epithelial cells
Supplementation of myo-inositol oxygenase (MIOX) inhibitor d-glucarate decreased MIOX expression, attenuated tubular damage, reduced oxidative stress, restored mitophagy, and improved renal functions [194]. These studies suggest that inhibition of MIOX may play an important role in mitochondrial quality control and mitophagy in the pathogenesis of diabetic kidney disease (DKD), and that d-glucarate may serve as a potential therapeutic agent for the amelioration of DKD
Summary
Reactive oxygen species (ROS) are short-lived oxygen-containing molecules that are generated by enzymatic and non-enzymatic redox reactions during cellular aerobic metabolism [1,2]. One of the most important biological responses in the cell that is regulated by ROS and oxidative stress is autophagy. Stress-induced autophagy generally provides a protective role by eliminating and recycling damaged macromolecules, protein aggregates, and dysfunctional organelles [12,13,14]. The ROS produced upon degradation of ferritin by autophagy promote the cell death process known as ferroptosis [19]. The NO radical is produced by three isoforms of nitric oxide synthase (NOS), all of which are expressed in the kidney [31]. It serves a role as a potent vasodilator and is involved in the regulation of hypertension. Increasing NO levels can further react with O2− to produce ONOO−, which can cause protein nitration [32]
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