Murine double nullizygotes of the angiotensin type 1A and 1B receptor genes duplicate severe abnormal phenotypes of angiotensinogen nullizygotes
Murine double nullizygotes of the angiotensin type 1A and 1B receptor genes duplicate severe abnormal phenotypes of angiotensinogen nullizygotes
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DOI：
10.1172/jci1899
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发表时间：
1998-02-15
影响因子：
15.9
通讯作者：
Ichikawa, L
中科院分区：
文献类型：
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作者：
Tsuchida, S;Matsusaka, T;Ichikawa, L
啮齿类动物是唯一携带重复的血管紧张素（Ang）1型（AT 1）受体基因Agtr 1a和Agtr 1b的物种。通过基因打靶分别产生Agtr 1a和Agtr 1b无效突变小鼠，通过交配产生Agtr 1a和Agtr 1b无效突变的双突变小鼠（Agtr 1a-/-; Agtr 1b-/-）。Agtr 1a-/-、Agtr 1b-/-小鼠的特征为宫内存活正常，但宫内存活率降低。出生后，其特征在于低体重增加、显著低血压和异常肾脏形态，包括肾小球生长延迟成熟、乳头发育不良和肾动脉肥大。这些异常表型在数量上与血管紧张素原基因（Agt-/-）纯合子突变小鼠中发现的相似，表明由Agt-/-异常表型阐明的内源性Ang的主要生物学功能是由AT 1受体介导的。输注Ang II、AT 1阻断剂或AT 2阻断剂对Agtr 1a-/-; Agtr 1b-/-小鼠的血压没有影响，表明AT 2受体在这些缺乏AT 1受体的小鼠中不发挥急性降压作用。此外，与Agt-/-小鼠不同，一些Agtr 1a-/-; Agtr 1b-/-小鼠具有较大的室间隔缺损，这表明另一种受体如AT 2在Agtr 1a-/-，Agtr 1b-/-小鼠中功能性激活。
Rodents are the unique species carrying duplicated angiotensin (Ang) type 1 (AT1) receptor genes, Agtr1a and Agtr1b, After separately generating Agtr1a and Agtr1b null mutant mice by gene targeting, we produced double mutant mice homozygous for both Agtr1a and Agtr1b null mutation (Agtr1a-/-; Agtr1b-/-) by mating the single gene mutants. Agtr1a-/-, Agtr1b-/- mice are characterized by normal in utero survival but decreased ex utero survival rate. After birth they are characterized by low body weight gain, marked hypotension, and abnormal kidney morphology including delayed maturity in glomerular growth, hypoplastic papilla, and renal arterial hypertrophy. These abnormal phenotypes are quantitatively similar to those found in mutant mice homozygous for the angiotensinogen gene (Agt-/-), indicating that major biological functions of endogenous Ang elucidated by the abnormal phenotypes of Agt-/- are mediated by the AT1 receptors. Infusion of Ang II, AT1 blockers, or an AT2 blocker was without effect on blood pressure in Agtr1a-/-; Agtr1b-/- mice, indicating that AT2 receptor does not exert acute depressor effects in these mice lacking AT1 receptors. Also, unlike Agt-/- mice, some Agtr1a-/-; Agtr1b-/- mice have a large ventricular septum defect, suggesting that another receptor such as AT2 is functionally activated in Agtr1a-/-, Agtr1b-/- mice.