title: The balance of powers: Redox regulation of fibrogenic pathways in kidney injury.
abstract: Oxidative stress plays a central role in the pathogenesis of diverse chronic inflammatory disorders including diabetic complications, cardiovascular disease, aging, and chronic kidney disease (CKD). Patients with moderate to advanced CKD have markedly increased levels of oxidative stress and inflammation that likely contribute to the unacceptable high rates of morbidity and mortality in this patient population. Oxidative stress is defined as an imbalance of the generation of reactive oxygen species (ROS) in excess of the capacity of cells/tissues to detoxify or scavenge them. Such a state of oxidative stress may alter the structure/function of cellular macromolecules and tissues that eventually leads to organ dysfunction. The harmful effects of ROS have been largely attributed to its indiscriminate, stochastic effects on the oxidation of protein, lipids, or DNA but in many instances the oxidants target particular amino acid residues or lipid moieties. Oxidant mechanisms are intimately involved in cell signaling and are linked to several key redox-sensitive signaling pathways in fibrogenesis. Dysregulation of antioxidant mechanisms and overproduction of ROS not only promotes a fibrotic milieu but leads to mitochondrial dysfunction and further exacerbates kidney injury. Our studies support the hypothesis that unique reactive intermediates generated in localized microenvironments of vulnerable tissues such as the kidney activate fibrogenic pathways and promote end-organ damage. The ability to quantify these changes and assess response to therapies will be pivotal in understanding disease mechanisms and monitoring efficacy of therapy.
authors.affiliation: Seattle Children's Research Institute, Department of Pediatrics, University of Washington, Seattle, WA, USA. Electronic address: daryl.okamura@seattlechildrens.org.
authors.forename: Daryl M
authors.initials: DM
authors.lastname: Okamura
authors.affiliation: University of Michigan, Department of Medicine, Division of Nephrology, Ann Arbor, MI, USA.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Pennathur
mesh_terms: D000818:Animals; D005355:Fibrosis; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species
keywords: Chronic kidney disease; Fibrosis; Mass spectrometry; Oxidative stress; Oxidized amino acids