Klotho Regulates Cigarette Smoke-Induced Autophagy: Implication in Pathogenesis of COPD.

INTRODUCTION: Chronic obstructive pulmonary disease is a progressive lung disease characterized by abnormal cellular responses to cigarette smoke, resulting in tissue destruction and airflow limitation. Autophagy is a fundamental cellular process that eliminates long-lived proteins and damaged organelles through lysosomal degradation pathway, though its role in human diseases remains unclear. We hypothesized that an anti-aging protein, Klotho plays an important role in regulating autophagy in response to cigarette smoke (CS).
METHODS: Autophagy was measured by detecting LC3-I and LC3-II expressions. The regulation of autophagy expression by cigarette smoke extract (CSE) was studied in vitro, and small-interfering RNA (siRNA) and recombinant Klotho were employed to investigate the role of Klotho on CSE-induced autophagy. Protein levels and phosphorylation were measured by Western blot assay.
RESULTS: CS exposure resulted in induction of autophagy in alveolar macrophages. Pretreatment of cells with Klotho attenuated CS-induced autophagy whereas knockdown of Klotho augmented CS-induced autophagy. Klotho inhibited phosphorylation of ERK, Akt, and IGF-1 in CSE-stimulated cells.
CONCLUSIONS: These data suggest that Klotho plays a critical role in the regulation of CS-induced autophagy and have important implications in understanding the mechanisms of CS-induced cell death and senescence.