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 6

Impaired lung morphology and function of Et2-null mice.

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Impaired lung morphology and function of Et2-null mice. (A and B) qRT-...
(A and B) qRT-PCR was performed using mRNAs extracted from isolated epithelial and mesenchymal cell populations of rat lung to examine the purity of cell fractions (A) and expression of ET-2, ETA, and ETB (B) (n = 3–5). Values are presented as fold change relative to gene expression in epithelium for Krt18, Et2, Eta, and Etb, and in mesenchyme for Vim. (C) Histological phenotypes of the lungs of Et2-null and littermate WT mice. Lung sections from constitutive Et2-null (P1-P21) and adult Et2f/f;CAGGCre-ERTM (8-week-old) mice and their control littermates were stained with H&E. Original magnification, ×10. (D) Blood gas of constitutive Et2-null (2-week-old) and adult Et2f/f;CAGGCre-ERTM (8-week-old) mice and their control littermates (n = 6). (E–G) Levels of erythropoietin (Epo) mRNA in kidneys (left) and protein in serum (right) (E), hematocrit (Hct) (F) level, and total lung capacity (G) of constitutive Et2-null and control littermate mice at 3 weeks of age (n = 5). *P < 0.05; **P < 0.01; #P < 0.001.