αKlotho deficiency in acute kidney injury contributes to lung damage

alpha Klotho 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 alpha Klotho deficiency. Because acute lung injury is a common and serious complication of acute kidney injury (AKI), we hypothesized that alpha Klotho 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 alpha Klotho-containing conditioned media 6 h post-AKI did not alter plasma creatinine but improved recovery of endogenous alpha Klotho production 3 days post-AKI, reduced lung edema and oxidative damage, and increased endogenous antioxidative capacity in the lung. Intravenously injected alpha Klotho rapidly exits alveolar capillaries as a macromolecule, suggesting transcytosis and direct access to the epithelium. To explore the epithelial action of alpha Klotho, we simulated oxidative stress in vitro by adding hydrogen peroxide to cultured A549 lung epithelial cells. Purified recombinant alpha Klotho directly protected cells at 20 pM with half-maximal effects at 40-50 pM, which is compatible with circulating alpha Klotho levels. Addition of recombinant alpha Klotho 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, alpha Klotho deficiency in AKI contributes to acute lung injury by reducing endogenous antioxidative capacity and increasing oxidative damage in the lung. alpha Klotho replacement partially reversed these abnormalities and mitigated pulmonary complications in AKI.