Increased Akt-mTOR signaling in lung epithelium is associated with respiratory distress syndrome in mice

Hiroyuki Ikeda, Ichiro Shiojima, Toru Oka, Masashi Yoshida, Koji Maemura, Kenneth Walsh, Takashi Igarashi, Issei Komuro

Research output: Contribution to journalArticle

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Abstract

Pregnancy in women with diabetes is associated with a higher risk of perinatal complications. In particular, infants of diabetic mothers frequently suffer from respiratory distress syndrome (RDS), which is a leading cause of death in preterm infants and is considered to be primarily due to hyperinsulinemia in infants in response to maternal hyperglycemia. To elucidate the mechanism of how insulin signaling induces RDS, bronchoalveolar epithelium-specific Akt1 transgenic (TG) mice were generated. Akt1 overexpression in fetal lung epithelium resulted in RDS in preterm infants born by Caesarean section at embryonic day 18.5 (E18.5). The expression levels of hypoxia-inducible factor 2α (HIF-2α) and its target vascular endothelial growth factor (VEGF) were downregulated in the lung of Akt1 TG mice. Inhibition of the Akt-mammalian target of rapamycin (mTOR) signaling axis by rapamycin restored the expression of VEGF and improved the lung pathology of Akt1 TG pups. Rapamycin also attenuated the RDS phenotype in wild-type mice delivered preterm at E17.5. In cultured lung epithelial cells, insulin reduced VEGF expression and transcriptional activity of HIF-2 on VEGF promoter in an mTOR-dependent manner. Thus, aberrant activation of the Akt-mTOR pathway in lung epithelium plays a causal role in the pathogenesis of infant RDS, presumably through downregulation of HIF-2-dependent VEGF expression in the lung.

Original languageEnglish
Pages (from-to)1054-1065
Number of pages12
JournalMolecular and Cellular Biology
Volume31
Issue number5
DOIs
Publication statusPublished - Mar 1 2011
Externally publishedYes

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Sirolimus
Epithelium
Vascular Endothelial Growth Factor A
Lung
Premature Infants
Transgenic Mice
Down-Regulation
Mothers
Insulin
Newborn Respiratory Distress Syndrome
Hyperinsulinism
Cesarean Section
Hyperglycemia
Cause of Death
Epithelial Cells
Pathology
Phenotype
Pregnancy
endothelial PAS domain-containing protein 1

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Increased Akt-mTOR signaling in lung epithelium is associated with respiratory distress syndrome in mice. / Ikeda, Hiroyuki; Shiojima, Ichiro; Oka, Toru; Yoshida, Masashi; Maemura, Koji; Walsh, Kenneth; Igarashi, Takashi; Komuro, Issei.

In: Molecular and Cellular Biology, Vol. 31, No. 5, 01.03.2011, p. 1054-1065.

Research output: Contribution to journalArticle

Ikeda, Hiroyuki ; Shiojima, Ichiro ; Oka, Toru ; Yoshida, Masashi ; Maemura, Koji ; Walsh, Kenneth ; Igarashi, Takashi ; Komuro, Issei. / Increased Akt-mTOR signaling in lung epithelium is associated with respiratory distress syndrome in mice. In: Molecular and Cellular Biology. 2011 ; Vol. 31, No. 5. pp. 1054-1065.
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