Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Aging (Upcoming)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
Endothelin-2 deficiency causes growth retardation, hypothermia, and emphysema in mice
Inik Chang, … , Roderick R. McInnes, Masashi Yanagisawa
Inik Chang, … , Roderick R. McInnes, Masashi Yanagisawa
Published May 8, 2013
Citation Information: J Clin Invest. 2013;123(6):2643-2653. https://doi.org/10.1172/JCI66735.
View: Text | PDF
Research Article Endocrinology

Endothelin-2 deficiency causes growth retardation, hypothermia, and emphysema in mice

  • Text
  • PDF
Abstract

To explore the physiological functions of endothelin-2 (ET-2), we generated gene-targeted mouse models. Global Et2 knockout mice exhibited severe growth retardation and juvenile lethality. Despite normal milk intake, they suffered from internal starvation characterized by hypoglycemia, ketonemia, and increased levels of starvation-induced genes. Although ET-2 is abundantly expressed in the gastrointestinal tract, the intestine was morphologically and functionally normal. Moreover, intestinal epithelium–specific Et2 knockout mice showed no abnormalities in growth and survival. Global Et2 knockout mice were also profoundly hypothermic. Housing Et2 knockout mice in a warm environment significantly extended their median lifespan. However, neuron-specific Et2 knockout mice displayed a normal core body temperature. Low levels of Et2 mRNA were also detected in the lung, with transient increases soon after birth. The lungs of Et2 knockout mice showed emphysematous structural changes with an increase in total lung capacity, resulting in chronic hypoxemia, hypercapnia, and increased erythropoietin synthesis. Finally, systemically inducible ET-2 deficiency in neonatal and adult mice fully reproduced the phenotype previously observed in global Et2 knockout mice. Together, these findings reveal that ET-2 is critical for the growth and survival of postnatal mice and plays important roles in energy homeostasis, thermoregulation, and the maintenance of lung morphology and function.

Authors

Inik Chang, Alexa N. Bramall, Amy Greenstein Baynash, Amir Rattner, Dinesh Rakheja, Martin Post, Stephen Joza, Colin McKerlie, Duncan J. Stewart, Roderick R. McInnes, Masashi Yanagisawa

×

Figure 1

Expression profile of Et2 mRNA.

Options: View larger image (or click on image) Download as PowerPoint
Expression profile of Et2 mRNA.
 
(A) qRT-PCR analysis of Et2 mRNA expre...
(A) qRT-PCR analysis of Et2 mRNA expression in individual tissues and time course in the embryo and lung (n = 5). Values are presented as fold change relative to ET-2 expression in E10 (whole embryo), BAT (thermoregulatory tissues), P20 (lung), and muscle (whole tissues). (B and C) Localization of ET-2, ETA, and ETB in small intestine. In situ hybridization was performed with 35S-labeled probes in the mouse ileum. (B) Representative photographs shown by dark-field microscopic imaging. Original magnification, ×20. Constitutive Et2-null mouse (KO) was used as a negative control. (C) Representative photographs shown by bright-field microscopic imaging. Original magnification, ×40. Black dots indicate the localization of genes, and arrows show specific localization of ET-2 in the villous and crypt epithelium, and ETA and ETB in the lamina propria.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts