RGD Reference Report - Endothelin-1 impairs alveolar epithelial function via endothelial ETB receptor. - Rat Genome Database

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Endothelin-1 impairs alveolar epithelial function via endothelial ETB receptor.

Authors: Comellas, AP  Briva, A  Dada, LA  Butti, ML  Trejo, HE  Yshii, C  Azzam, ZS  Litvan, J  Chen, J  Lecuona, E  Pesce, LM  Yanagisawa, M  Sznajder, JI 
Citation: Comellas AP, etal., Am J Respir Crit Care Med. 2009 Jan 15;179(2):113-22. Epub 2008 Oct 23.
RGD ID: 4892575
Pubmed: PMID:18948426   (View Abstract at PubMed)
PMCID: PMC2633058   (View Article at PubMed Central)
DOI: DOI:10.1164/rccm.200804-540OC   (Journal Full-text)

RATIONALE: Endothelin-1 (ET-1) is increased in patients with high-altitude pulmonary edema and acute respiratory distress syndrome, and these patients have decreased alveolar fluid reabsorption (AFR). OBJECTIVES: To determine whether ET-1 impairs AFR via activation of endothelial cells and nitric oxide (NO) generation. METHODS: Isolated perfused rat lung, transgenic rats deficient in ETB receptors, coincubation of lung human microvascular endothelial cells (HMVEC-L) with rat alveolar epithelial type II cells or A549 cells, ouabain-sensitive 86Rb+ uptake. MEASUREMENTS AND MAIN RESULTS: The ET-1-induced decrease in AFR was prevented by blocking the endothelin receptor ETB, but not ETA. Endothelial-epithelial cell interaction is required, as direct exposure of alveolar epithelial cells (AECs) to ET-1 did not affect Na,K-ATPase function or protein abundance at the plasma membrane, whereas coincubation of HMVEC-L and AECs with ET-1 decreased Na,K-ATPase activity and protein abundance at the plasma membrane. Exposing transgenic rats deficient in ETB receptors in the pulmonary vasculature (ET-B(-/-)) to ET-1 did not decrease AFR or Na,K-ATPase protein abundance at the plasma membrane of AECs. Exposing HMVEC-L to ET-1 led to increased NO, and the ET-1-induced down-regulation of Na,K-ATPase was prevented by the NO synthase inhibitor l-NAME, but not by a guanylate cyclase inhibitor. CONCLUSIONS: We provide the first evidence that ET-1, via an endothelial-epithelial interaction, leads to decreased AFR by a mechanism involving activation of endothelial ETB receptors and NO generation leading to alveolar epithelial Na,K-ATPase down-regulation in a cGMP-independent manner.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Edn1Ratepithelial fluid transport  IDA  RGD 
EdnrbRatepithelial fluid transport  IMP  RGD 
Edn1Ratmaternal process involved in parturition  IEP  RGD 
EdnraRatmaternal process involved in parturition  IEP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Edn1  (endothelin 1)
Ednra  (endothelin receptor type A)
Ednrb  (endothelin receptor type B)


Additional Information