Kidney-specific enhancement of ANG II stimulates endogenous intrarenal angiotensinogen in gene-targeted mice
Kidney-specific enhancement of ANG II stimulates endogenous intrarenal angiotensinogen in gene-targeted mice
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DOI：
10.1152/ajprenal.00146.2007
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发表时间：
2007-09-01
影响因子：
4.2
通讯作者：
Navar, L. Gabriel
中科院分区：
文献类型：
--
作者：
Kobori, Hiroyuki;Ozawa, Yuri;Navar, L. Gabriel
肾脏特异性增强ANG II刺激基因靶向小鼠内源性肾内血管紧张素原美国肾脏生理学杂志293：F938-F945，2007年。首次发表于2007年7月18日; doi：10.1152/ajprenal.00146.2007。本研究在转基因小鼠中进行，以检验以下假设：肾内ANG II的选择性过度产生增加肾内小鼠（m）血管紧张素原（AGT）表达。我们使用了以下三组：1）仅在肾脏中表达人（h）AGT的单转基因小鼠（A组，n = 14），2）除了仅在肾脏中表达hAGT之外还全身表达人肾素的双转基因小鼠（D组，n = 13），和3）野生型小鼠（W组，n = 12）。外源性hAGT蛋白在A组中是无活性的，因为内源性小鼠肾素由于高种属特异性而不能将hAGT切割成ANG I。从12至18周龄监测所有小鼠。D组的收缩压从116 ± 5 mmHg（12周）逐渐升高至140 ± 7 mmHg（18周）。在A组或W组中未观察到这种增加。A组和D组肾内hAGT水平相似;然而，W组肾脏中未检测到hAGT。与A组（117 +/- 16）和W组（118 +/- 17）相比，D组（216 +/- 43 fmol/g）的肾脏ANG II水平升高。然而，三组之间的血浆ANG II浓度相似。与A组（0.97 +/- 0.12）和W组（1.00 +/- 0.08）相比，D组（1.46 +/- 0.19，比值）的内源性肾脏mAGT mRNA显著增加。与A组和W组相比，D组的内源性肾脏mAGT蛋白也显着增加。与A组和W组相比，D组间质胶原阳性面积、间质巨噬细胞/单核细胞浸润和输入小动脉壁厚度显著增加。这些数据表明，第一次选择性刺激肾内产生的血管紧张素II从hAGT增强内源性肾内mAGT mRNA和蛋白质的表达。
Kidney-specific enhancement of ANG II stimulates endogenous intrarenal angiotensinogen in gene-targeted mice. Am J Physiol Renal Physiol 293: F938-F945, 2007. First published July 18, 2007; doi:10.1152/ajprenal.00146.2007.- This study was performed in transgenic mice to test the hypothesis that the selective intrarenal overproduction of ANG II increases intrarenal mouse ( m) angiotensinogen (AGT) expression. We used the following three groups: 1) single transgenic mice ( group A, n = 14) expressing human ( h) AGT only in the kidney, 2) double-transgenic mice ( group D, n = 13) expressing human renin systemically in addition to hAGT only in the kidney, and 3) wild-type ( group W, n = 12) mice. Exogenous hAGT protein is inactive in group A because endogenous mouse renin cannot cleave hAGT to ANG I because of a high species specificity. All mice were monitored from 12 to 18 wk of age. Systolic blood pressure progressively increased from 116 +/- 5 mmHg ( 12 wk) to 140 +/- 7 ( 18 wk) in group D. This increase was not observed in groups A or W. Intrarenal hAGT levels were similar in groups A and D; however, hAGT was not detectable in kidneys of group W. Kidney ANG II levels were increased in group D ( 216 +/- 43 fmol/g) compared with groups A ( 117 +/- 16) and W ( 118 +/- 17). However, plasma ANG II concentrations were similar among the three groups. Endogenous renal mAGT mRNA was increased significantly in group D ( 1.46 +/- 0.19, ratio) compared with groups A ( 0.97 +/- 0.12) and W ( 1.00 +/- 0.08). Endogenous renal mAGT protein was also significantly increased in group D compared with groups A and W. Interstitial collagen-positive area, interstitial macrophage/monocyte infiltration, and afferent arteriolar wall thickness were increased significantly in group D compared with groups A and W. These data indicate for the first time that the selective stimulation of intrarenal production of ANG II from hAGT augments endogenous intrarenal mAGT mRNA and protein expression.