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.
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Research Article Endocrinology

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

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

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Figure 4

No detectable abnormalities in energy-related processes of constitutive and intestinal epithelium–specific Et2-null mice.

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No detectable abnormalities in energy-related processes of constitutive ...
(A) Dietary fat absorption (left) and excretion of fats and carbohydrates (right) of 6-week-old “rescued” constitutive Et2-null and littermate WT mice (n = 5). (B) qRT-PCR analysis demonstrating intestine-specific deletion of Et2 by villin promoter–driven Cre recombinase (n = 5). Values are presented as fold change relative to ET-2 expression in stomach from control Et2f/f mice. (C) Body weight of Et2f/f;Vil-Cre and their littermate control Et2f/f mice (n = 21–23). (D) Blood glucose levels of Et2f/f;Vil-Cre and their littermate control Et2f/f mice at 2 weeks of age (n = 10). (E) Dietary fat absorption (left) and excretion of fats and carbohydrates (right) of 6-week-old Et2f/f;Vil-Cre mice and their littermate controls (n = 5). ND, not detected; NS, nonsignificant.