Protective Role for Antioxidants in Acute Kidney Disease

Abstract

Acute kidney injury causes significant morbidity and mortality in the community and clinic. Various pathologies, including renal and cardiovascular disease, traumatic injury/rhabdomyolysis, sepsis, and nephrotoxicity, that cause acute kidney injury (AKI), induce general or regional decreases in renal blood flow. The ensuing renal hypoxia and ischemia promotes the formation of reactive oxygen species (ROS) such as superoxide radical anions, peroxides, and hydroxyl radicals, that can oxidatively damage biomolecules and membranes, and affect organelle function and induce renal tubule cell injury, inflammation, and vascular dysfunction. Acute kidney injury is associated with increased oxidative damage, and various endogenous and synthetic antioxidants that mitigate source and derived oxidants are beneficial in cell-based and animal studies. However, the benefit of synthetic antioxidant supplementation in human acute kidney injury and renal disease remains to be realized. The endogenous low-molecular weight, non-proteinaceous antioxidant, ascorbate (vitamin C), is a promising therapeutic in human renal injury in critical illness and nephrotoxicity. Ascorbate may exert significant protection by reducing reactive oxygen species and renal oxidative damage via its antioxidant activity, and/or by its non-antioxidant functions in maintaining hydroxylase and monooxygenase enzymes, and endothelium and vascular function. Ascorbate supplementation may be particularly important in renal injury patients with low vitamin C status.

Keywords: antioxidant; endothelium; hypoxia; ischemia; oxidant; renal injury; vitamin C.

Figure 1

Increased reactive oxygen species (ROS) levels in acute kidney injury (AKI) induce renal oxidative damage and injury. Hypoxia and ischemia perturb microcirculation, cellular enzymes, and mitochondrial function, supporting production of intracellular ROS such as O₂^•− and H₂O₂, resulting in mitochondrial damage, depletion of ATP, and activation of cell death pathways. Reperfusion after ischemia also increases ROS. Ischemic injury activates endothelial cells up-regulating pro-inflammatory cytokines and recruiting phagocytes that contribute ROS via NOX and MPO. Inflammation induces ROS and iNOS, promoting peroxynitrite formation. Trauma and toxins generate oxidative stress by depleting endogenous antioxidants and increasing redox-active metal ions. Vascular dysfunction promoted by ischemia, inflammation, or toxicity, affects eNOS function, inducing ROS generation. ROS perturb kinase/phosphatase activities and transcription factor signaling pathways important in cell homeostasis. Oxidative modification of membranes and proteins disrupts cell ion and nutrient transport, energy metabolism, and organelle function, ultimately affecting kidney viability.

Figure 2

Key activities of vitamin C and proposed benefit mechanisms in acute renal injury. BH4 = tetrahydrobiopterin; RNS = reactive nitrogen species; CI-AKI = chemical induced acute kidney injury