Klotho, an antiaging molecule, attenuates oxidant-induced alveolar epithelial cell mtDNA damage and apoptosis

Seok Jo Kim, Paul Cheresh, Mesut Eren, Renea P. Jablonski, Anjana Yeldandi, Karen M. Ridge, G. R. Scott Budinger, Dong Hyun Kim, Myles Wolf, Douglas E. Vaughan, David W. Kamp*

*Corresponding author for this work

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Alveolar epithelial cell (AEC) apoptosis and inadequate repair resulting from “exaggerated” lung aging and mitochondrial dysfunction are critical determinants promoting lung fibrosis. α-Klotho, which is an antiaging molecule that is expressed predominantly in the kidney and secreted in the blood, can protect lung epithelial cells against hyperoxia-induced apoptosis. We reasoned that Klotho protects AEC exposed to oxidative stress in part by maintaining mitochondrial DNA (mtDNA) integrity and mitigating apoptosis. We find that Klotho levels are decreased in both serum and alveolar type II (AT2) cells from asbestos-exposed mice. We show that oxidative stress reduces AEC Klotho mRNA and protein expression whereas Klotho overexpression is protective while Klotho silencing augments AEC mtDNA damage. Compared with wild-type Klotho heterozygous hypomorphic allele (kl/+) mice have increased asbestos-induced lung fibrosis due in part to increased AT2 cell mtDNA damage. Notably, we demonstrate that serum Klotho levels are reduced in wild-type but not mitochondrial catalase overexpressing (MCAT) mice 3 wk following exposure to asbestos and that EUK-134, a MnSOD/catalase mimetic, mitigates oxidant-induced reductions in AEC Klotho expression. Using pharmacologic and genetic silencing studies, we show that Klotho attenuates oxidantinduced AEC mtDNA damage and apoptosis via mechanisms dependent on AKT activation arising from upstream fibroblast growth factor receptor 1 activation. Our findings suggest that Klotho preserves AEC mtDNA integrity in the setting of oxidative stress necessary for preventing apoptosis and asbestos-induced lung fibrosis. We reason that strategies aimed at augmenting AEC Klotho levels may be an innovative approach for mitigating age-related lung diseases.

Original languageEnglish (US)
Pages (from-to)L16-L26
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume313
Issue number1
DOIs
StatePublished - Jan 1 2017

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Keywords

  • Alveolar epithelial cell
  • Klotho
  • Mitochondrial DNA damage
  • Oxidative stress
  • Pulmonary fibrosis

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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