miR-210 promotes IPF fibroblast proliferation in response to hypoxia

Vidya Bodempudi, Polla Hergert, Karen Smith, Hong Xia, Jeremy Herrera, Mark Peterson, Wajahat Khalil, Judy Kahm, Peter B. Bitterman, Craig A. Henke

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by the relentless spread of fibroblasts from scarred alveoli into adjacent alveolar units, resulting in progressive hypoxia and death by asphyxiation. Although hypoxia is a prominent clinical feature of IPF, the role of hypoxia as a driver of the progressive fibrotic nature of the disease has not been explored. Here, we demonstrate that hypoxia robustly stimulates the proliferation of IPF fibroblasts. We found that miR-210 expression markedly increases in IPF fibroblasts in response to hypoxia and that knockdown of miR-210 decreases hypoxia-induced IPF fibroblast proliferation. Silencing hypoxia-inducible factor (HIF)-2α inhibits the hypoxia-mediated increase in miR-210 expression and blocks IPF fibroblast proliferation, indicating that HIF-2α is upstream of miR-210. We demonstrate that the miR-210 downstream target MNT is repressed in hypoxic IPF fibroblasts and that knockdown of miR-210 increases MNT expression. Overexpression of MNT inhibits hypoxia-induced IPF fibroblast proliferation. Together, these data indicate that hypoxia potently stimulates miR-210 expression via HIF-2α, and high miR-210 expression drives fibroblast proliferation by repressing the c-myc inhibitor, MNT. In situ analysis of IPF lung tissue demonstrates miR-210 expression in a similar distribution with HIF-2α and the hypoxic marker carbonic anhydrase-IX in cells within the IPF fibrotic reticulum. Our results raise the possibility that a pathological feed-forward loop exists in the IPF lung, in which hypoxia promotes IPF fibroblast proliferation via stimulation of miR-210 expression, which in turn worsens hypoxia.

Original languageEnglish (US)
Pages (from-to)L283-L294
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume307
Issue number4
DOIs
StatePublished - Aug 15 2014

Keywords

  • Fibroblast proliferation
  • Hypoxia
  • Idiopathic pulmonary fibrosis
  • miR-210

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