Klotho protects against oxidative damage via amelioration of phosphotoxicity

Abstract

Klotho mitigates aging in various organs via a host of mechanisms including anti‐oxidation and anti‐phosphotoxicity. Organ damage in Klotho‐deficient animals can be rescued by dietary phosphate (Pi) restriction. The pulmonary epithelium is exposed to constant environmental insults. Klotho‐deficient animals exhibit alveolar airspace enlargement suggesting accelerated aging. To test the direct effects of Klotho against O2 and Pi toxicity in vitro, we exposed A549 lung epithelial cells to hyperoxia (95‐5% O2‐CO2) and increasing Pi (1, 3, 5 mM). Soluble (truncated) or transmembrane (full length) Klotho was over‐expressed by transfection. Apoptosis was measured from caspase‐8 activity (Table, nmol.[hr.104 cells]−1, mean±SD).Both hyperoxia and Pi induce apoptosis in A549 cells; the effects are synergistic (p<0.05, repeated measures ANOVA with respect to O2 and Pi). Both transmembrane and soluble Klotho overexpression markedly reduced cell apoptosis induced by Pi loading especially in hyperoxia. We conclude that Klotho exerts direct cytoprotective effects on pulmonary epithelium via anti‐oxidative and anti‐phosphotoxic effects.Support: F32 HL103043, RO1 DK091392, DK092461