title: αKlotho deficiency in acute kidney injury contributes to lung damage.
abstract: αKlotho is a circulating protein that originates predominantly from the kidney and exerts cytoprotective effects in distant sites. We previously showed in rodents that the lung is particularly vulnerable to αKlotho deficiency. Because acute lung injury is a common and serious complication of acute kidney injury (AKI), we hypothesized that αKlotho deficiency in AKI contributes to lung injury. To test the hypothesis, we created AKI by renal artery ischemia-reperfusion in rats and observed the development of alveolar interstitial edema and increased pulmonary oxidative damage to DNA, protein, and lipids. Administration of αKlotho-containing conditioned media 6 h post-AKI did not alter plasma creatinine but improved recovery of endogenous αKlotho production 3 days post-AKI, reduced lung edema and oxidative damage, and increased endogenous antioxidative capacity in the lung. Intravenously injected αKlotho rapidly exits alveolar capillaries as a macromolecule, suggesting transcytosis and direct access to the epithelium. To explore the epithelial action of αKlotho, we simulated oxidative stress in vitro by adding hydrogen peroxide to cultured A549 lung epithelial cells. Purified recombinant αKlotho directly protected cells at 20 pM with half-maximal effects at 40-50 pM, which is compatible with circulating αKlotho levels. Addition of recombinant αKlotho activated an antioxidant response element reporter and increased the levels of target proteins of the nuclear factor erythroid-derived 2 related factor system. In summary, αKlotho deficiency in AKI contributes to acute lung injury by reducing endogenous antioxidative capacity and increasing oxidative damage in the lung. αKlotho replacement partially reversed these abnormalities and mitigated pulmonary complications in AKI.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas; and Priya.Ravikumar@utsouthwestern.edu.
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, Texas; and.
authors.forename: Liping
authors.initials: L
authors.lastname: Li
authors.affiliation: Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas; and.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Ye
authors.affiliation: Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas; and.
authors.forename: Mingjun
authors.initials: M
authors.lastname: Shi
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas; and.
authors.forename: Masatomo
authors.initials: M
authors.lastname: Taniguchi
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas; and.
authors.forename: Jianning
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas; and Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuro-o
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas; and.
authors.forename: Ming Chang
authors.initials: MC
authors.lastname: Hu
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas; Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas; and.
authors.forename: Orson W
authors.initials: OW
authors.lastname: Moe
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas.
authors.forename: Connie C W
authors.initials: CC
authors.lastname: Hsia
mesh_terms: D000072283:A549 Cells; D058186:Acute Kidney Injury / Q000378:metabolism*; D055371:Acute Lung Injury / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D004195:Disease Models, Animal; D007668:Kidney / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000172:deficiency*
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D011956:Receptors, Cell Surface
keywords: antioxidant response element; cytoprotection; nuclear factor erythroid-derived 2 transcription factor; oxidative stress; total antioxidant capacity