alpha-Klotho protects against oxidative damage in pulmonary epithelia

作者：Ravikumar Priya; Ye Jianfeng; Zhang Jianning; Pinch Sydney N; Hu Ming Chang; Kuro o Makoto; Hsia Connie C W; Moe Orson W^*

来源：American Journal of Physiology - Lung Cellular and Molecular Physiology, 2014, 307(7): L566-L575.

DOI：10.1152/ajplung.00306.2013

• lung injury
• hyperoxia
• phosphate toxicity
• Klotho cytoprotection
• alveolar epithelial cells
• antioxidant capacity

alpha-Klotho exerts pleiotropic biological actions. Heterozygous alpha-Klotho haplo-insufficient mice (kl/+) appear normal at baseline except for age-related changes in the lung, suggesting heightened pulmonary susceptibility to alpha-Klotho deficiency. We used in vivo and in vitro models to test whether alpha-Klotho protects lung epithelia against injury. Normally, alpha-Klotho is not expressed in the lung, but circulating alpha-Klotho levels are reduced similar to 40% in kl/+ mice and undetectable in homozygous alpha-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-2) and high inorganic phosphate concentrations (Pi, 3-5 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 alpha-Klotho, or addition of soluble alpha-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 alpha-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 alpha-Klotho protects the lung against oxidative damage and apoptosis partly via increasing endogenous antioxidative capacity in pulmonary epithelia. Cytoprotection by alpha-Klotho may play an important role in degenerative diseases of the lung.

• 出版日期2014-10-1