TY - JOUR
T1 - Endothelin-2 deficiency causes growth retardation, hypothermia, and emphysema in mice
AU - Chang, Inik
AU - Bramall, Alexa N.
AU - Baynash, Amy Greenstein
AU - Rattner, Amir
AU - Rakheja, Dinesh
AU - Post, Martin
AU - Joza, Stephen
AU - McKerlie, Colin
AU - Stewart, Duncan J.
AU - McInnes, Roderick R.
AU - Yanagisawa, Masashi
PY - 2013/6/3
Y1 - 2013/6/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84878584063&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84878584063&partnerID=8YFLogxK
U2 - 10.1172/JCI66735
DO - 10.1172/JCI66735
M3 - Article
C2 - 23676500
AN - SCOPUS:84878584063
SN - 0021-9738
VL - 123
SP - 2643
EP - 2653
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 6
ER -