{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T04:58:09Z","timestamp":1792645089611,"version":"4.5.0"},"reference-count":41,"publisher":"American Physiological Society","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"published-print":{"date-parts":[[2014,10,1]]},"abstract":"<jats:p> \u03b1-Klotho exerts pleiotropic biological actions. Heterozygous \u03b1-Klotho haplo-insufficient mice ( kl\/+) appear normal at baseline except for age-related changes in the lung, suggesting heightened pulmonary susceptibility to \u03b1-Klotho deficiency. We used in vivo and in vitro models to test whether \u03b1-Klotho protects lung epithelia against injury. Normally, \u03b1-Klotho is not expressed in the lung, but circulating \u03b1-Klotho levels are reduced \u223c40% in kl\/+ mice and undetectable in homozygous \u03b1-Klotho-deficient mice ( kl\/kl). kl\/+ mice show distal air space enlargement at a given airway pressure, with elevated lung oxidative damage marker (8-hydroxydeoxyguanosine; 8-OHdG); these abnormalities are exacerbated in kl\/kl mice. Studies were performed in A549 lung epithelial cells and\/or primary culture of alveolar epithelial cells. Hyperoxia (95% O<jats:sub>2<\/jats:sub>) and high inorganic phosphate concentrations (Pi, 3\u20135 mM) additively caused cell injury (lactate dehydrogenase release), oxidative DNA damage (8-OHdG), lipid oxidation (8-isoprostane), protein oxidation (carbonyl), and apoptosis (caspase-8 activity and TUNEL stain). Transfection of transmembrane or soluble \u03b1-Klotho, or addition of soluble \u03b1-Klotho-containing conditioned media, increased cellular antioxidant capacity (Cu- and Fe-based assays) via increased nuclear factor erythroid-derived 2-related factors 1 and 2 (Nrf1\/2) transcriptional activity and ameliorated hyperoxic and phosphotoxic injury. To validate the findings in vivo, we injected \u03b1-Klotho-containing conditioned media into rat peritoneum before and during hyperoxia exposure and found reduced alveolar interstitial edema and oxidative damage. We conclude that circulating \u03b1-Klotho protects the lung against oxidative damage and apoptosis partly via increasing endogenous antioxidative capacity in pulmonary epithelia. Cytoprotection by \u03b1-Klotho may play an important role in degenerative diseases of the lung. <\/jats:p>","DOI":"10.1152\/ajplung.00306.2013","type":"journal-article","created":{"date-parts":[[2014,7,26]],"date-time":"2014-07-26T03:18:57Z","timestamp":1406344737000},"page":"L566-L575","source":"Crossref","is-referenced-by-count":106,"title":["\u03b1-Klotho protects against oxidative damage in pulmonary epithelia"],"prefix":"10.1152","volume":"307","author":[{"given":"Priya","family":"Ravikumar","sequence":"first","affiliation":[{"name":"Departments of 1Internal Medicine,"},{"name":"Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfeng","family":"Ye","sequence":"additional","affiliation":[{"name":"Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianning","family":"Zhang","sequence":"additional","affiliation":[{"name":"Departments of 1Internal Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney N.","family":"Pinch","sequence":"additional","affiliation":[{"name":"Departments of 1Internal Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming Chang","family":"Hu","sequence":"additional","affiliation":[{"name":"Departments of 1Internal Medicine,"},{"name":"Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Kuro-o","sequence":"additional","affiliation":[{"name":"Pathology,"},{"name":"Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connie C. 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