Document Detail


Increased Akt-mTOR signaling in lung epithelium is associated with respiratory distress syndrome in mice.
MedLine Citation:
PMID:  21189286     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Hiroyuki Ikeda; Ichiro Shiojima; Toru Oka; Masashi Yoshida; Koji Maemura; Kenneth Walsh; Takashi Igarashi; Issei Komuro
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-12-28
Journal Detail:
Title:  Molecular and cellular biology     Volume:  31     ISSN:  1098-5549     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-02-10     Completed Date:  2011-04-07     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1054-65     Citation Subset:  IM    
Affiliation:
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Japan.
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MeSH Terms
Descriptor/Qualifier:
Animals
Basic Helix-Loop-Helix Transcription Factors / genetics,  metabolism
Cells, Cultured
Disease Models, Animal
Female
Humans
Infant, Newborn
Insulin / metabolism
Lung / enzymology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Pregnancy
Proto-Oncogene Proteins c-akt / genetics,  metabolism*
Respiratory Distress Syndrome, Newborn / enzymology*
Respiratory Mucosa / enzymology
Sirolimus / therapeutic use
TOR Serine-Threonine Kinases / genetics,  metabolism*
Vascular Endothelial Growth Factors / genetics,  metabolism
Chemical
Reg. No./Substance:
0/Basic Helix-Loop-Helix Transcription Factors; 0/Insulin; 0/Vascular Endothelial Growth Factors; 0/endothelial PAS domain-containing protein 1; 53123-88-9/Sirolimus; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.1.1/mTOR protein, mouse; EC 2.7.11.1/Akt1 protein, mouse; EC 2.7.11.1/Proto-Oncogene Proteins c-akt
Comments/Corrections

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