title: Acute lung injury complicating acute kidney injury: A model of endogenous αKlotho deficiency and distant organ dysfunction.
abstract: The lung interfaces with atmospheric oxygen via a large surface area and is perfused by the entire venous return bearing waste products collected from the whole body. It is logical that the lung is endowed with generous anti-oxidative capacity derived both locally and from the circulation. The single-pass pleiotropic alpha-Klotho (αKlotho) protein was discovered when its genetic disruption led to premature multi-organ degeneration and early death. The extracellular domain of αKlotho is cleaved by secretases and released into circulation as endocrine soluble αKlotho protein, exerting wide-ranging cytoprotective effects including anti-oxidation on distant organs including the lung, which exhibits high sensitivity to circulating αKlotho insufficiency. Because circulating αKlotho is derived mainly from the kidney, acute kidney injury (AKI) leads to systemic αKlotho deficiency that in turn increases the risks of pulmonary complications, i.e., edema and inflammation, culminating in the acute respiratory distress syndrome. Exogenous αKlotho increases endogenous anti-oxidative capacity partly via activation of the Nrf2 pathway to protect lungs against injury caused by direct hyperoxia exposure or AKI. This article reviews the current knowledge of αKlotho antioxidation in the lung in the setting of AKI as a model of circulating αKlotho deficiency, an under-recognized condition that weakens innate cytoprotective defenses and contributes to the dysfunction in distant organs.
authors.affiliation: Department of Internal Medicine, Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9034, United States of America. Electronic address: Connie.Hsia@utsouthwestern.edu.
authors.forename: Connie C W
authors.initials: CCW
authors.lastname: Hsia
authors.affiliation: Department of Internal Medicine, Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9034, United States of America; Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-9034, United States of America.
authors.forename: Priya
authors.initials: P
authors.lastname: Ravikumar
authors.affiliation: Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-9034, United States of America.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Ye
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism*; D055371:Acute Lung Injury / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000378:metabolism*; D012128:Respiratory Distress Syndrome / Q000378:metabolism
chemical_list: D000975:Antioxidants
keywords: Acute respiratory distress syndrome; Antioxidation; Cytoprotection; Hyperoxia; Nrf2 antioxidants; Oxidative stress