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

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

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2643-2653
Number of pages11
JournalJournal of Clinical Investigation
Volume123
Issue number6
DOIs
StatePublished - Jun 3 2013

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Endothelin-2
Emphysema
Hypothermia
Knockout Mice
Growth
Starvation
Lung
Total Lung Capacity
Ketosis
Hypercapnia
Body Temperature Regulation
Intestinal Mucosa
Erythropoietin
Body Temperature
Hypoglycemia
Genes
Intestines
Gastrointestinal Tract
Milk
Homeostasis

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Endothelin-2 deficiency causes growth retardation, hypothermia, and emphysema in mice. / Chang, Inik; Bramall, Alexa N.; Baynash, Amy Greenstein; Rattner, Amir; Rakheja, Dinesh; Post, Martin; Joza, Stephen; McKerlie, Colin; Stewart, Duncan J.; McInnes, Roderick R.; Yanagisawa, Masashi.

In: Journal of Clinical Investigation, Vol. 123, No. 6, 03.06.2013, p. 2643-2653.

Research output: Contribution to journalArticle

Chang, I, Bramall, AN, Baynash, AG, Rattner, A, Rakheja, D, Post, M, Joza, S, McKerlie, C, Stewart, DJ, McInnes, RR & Yanagisawa, M 2013, 'Endothelin-2 deficiency causes growth retardation, hypothermia, and emphysema in mice', Journal of Clinical Investigation, vol. 123, no. 6, pp. 2643-2653. https://doi.org/10.1172/JCI66735
Chang, Inik ; Bramall, Alexa N. ; Baynash, Amy Greenstein ; Rattner, Amir ; Rakheja, Dinesh ; Post, Martin ; Joza, Stephen ; McKerlie, Colin ; Stewart, Duncan J. ; McInnes, Roderick R. ; Yanagisawa, Masashi. / Endothelin-2 deficiency causes growth retardation, hypothermia, and emphysema in mice. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 6. pp. 2643-2653.
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