Oxidant Mechanisms in Renal Injury and Disease

Abstract

Significance: A common link between all forms of acute and chronic kidney injuries, regardless of species, is enhanced generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) during injury/disease progression. While low levels of ROS and RNS are required for prosurvival signaling, cell proliferation and growth, and vasoreactivity regulation, an imbalance of ROS and RNS generation and elimination leads to inflammation, cell death, tissue damage, and disease/injury progression.

Recent advances: Many aspects of renal oxidative stress still require investigation, including clarification of the mechanisms which prompt ROS/RNS generation and subsequent renal damage. However, we currently have a basic understanding of the major features of oxidative stress pathology and its link to kidney injury/disease, which this review summarizes.

Critical issues: The review summarizes the critical sources of oxidative stress in the kidney during injury/disease, including generation of ROS and RNS from mitochondria, NADPH oxidase, and inducible nitric oxide synthase. The review next summarizes the renal antioxidant systems that protect against oxidative stress, including superoxide dismutase and catalase, the glutathione and thioredoxin systems, and others. Next, we describe how oxidative stress affects kidney function and promotes damage in every nephron segment, including the renal vessels, glomeruli, and tubules.

Future directions: Despite the limited success associated with the application of antioxidants for treatment of kidney injury/disease thus far, preventing the generation and accumulation of ROS and RNS provides an ideal target for potential therapeutic treatments. The review discusses the shortcomings of antioxidant treatments previously used and the potential promise of new ones. Antioxid. Redox Signal. 25, 119-146.

FIG. 1.

The illustration of the signaling cascade and subsequent effects that ROS and RNS promote in cells of the renal corpuscle, including podocytes, endothelial, and mesangial cells. *Increased ROS and RNS increase Ang II, creating a positive feedback loop. RNS, reactive nitrogen species; ROS, reactive oxygen species; VSMCs, vascular smooth muscle cells.

FIG. 2.

Depiction of the determining events that occur in a renal cell during oxidative stress that determine if the cell will undergo apoptosis or necrosis. Mild ROS and RNS stress induces apoptosis. As oxidative stress continues, cell and mitochondrial membranes are damaged and necrosis ensues. Various endogenous antioxidant systems can prevent apoptosis and necrosis by attenuating oxidative stress, including factors upregulated by NRF-2. NRF-2, nuclear factor E2-related factor.

FIG. 3.

A schematic of the effects ROS and RNS have on Na⁺ reabsorption throughout the renal nephron, including signaling effector molecules. While Na⁺ reabsorption is reduced in the PT, overall, oxidative stress results in enhanced sodium reabsorption in the kidney due to upregulated Na⁺ reabsorption in the mTAL, DT, and CD. Protein in the filtrate stimulates production of hydrogen peroxide in the tubule, especially in the medulla where hydrogen peroxide levels are alleviated. CD, collecting duct; DT, distal tubule; mTAL, medullary thick ascending limb; PT, proximal tubule.