Hypertension associated with decreased testosterone levels in natriuretic peptide receptor-A gene-knockout and gene-duplicated mutant mouse models.
Hypertension associated with decreased testosterone levels in natriuretic peptide receptor-A gene-knockout and gene-duplicated mutant mouse models.
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DOI：
10.1210/en.140.11.5112
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发表时间：
1999
期刊：
影响因子：
4.8
通讯作者：
K. Pandey;P. Oliver;N. Maeda;O. Smithies
中科院分区：
文献类型：
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作者：
K. Pandey;P. Oliver;N. Maeda;O. Smithies
缺乏编码利钠肽受体A（NPRA）的基因（Npr 1）的小鼠患有高血压，伴有血压升高和心脏肥大。特别是，Npr 1基因缺陷的雄性小鼠表现出与未治疗的人类高血压患者相似的致命血管事件。高血压男性的血清睾酮水平往往低于正常男性，但这种趋势的遗传基础尚不清楚。为了确定Npr 1基因的功能是否会影响睾酮水平，我们测量了缺乏功能性Npr 1基因的雄性高血压小鼠、具有两个拷贝的野生型动物和表达四个拷贝基因的基因重复的同窝小鼠的血清睾酮。在Npr 1基因敲除（零拷贝）小鼠中，血清睾酮水平比双拷贝对照小鼠低62%（80+/-10 ts. 120+/-14 ng/ml; P < 0.005）。四拷贝小鼠的血清睾酮水平是两拷贝野生型对照小鼠的144%（P < 0.005）。为了研究NPRA在睾丸类固醇生成中的作用，我们分析了心房利钠肽（ANP）依赖性鸟苷酸环化酶的激活，细胞内cGMP的积累，以及Npr 1基因零，两个或四个拷贝的动物的纯化的原代Leydig细胞中的睾酮生产。缺乏Npr 1基因的Leydig细胞没有显示ANP刺激的鸟苷酸环化酶激活或cGMP积累，也没有ANP依赖的睾酮产生。ANP刺激来自四拷贝雄性的Leydig细胞引起cGMP的产生是两拷贝野生型对应物的2倍（260+/-12 vs. 126+/-7 pmol/l x10（6）cells; P < 0.001）。同样地，四拷贝小鼠的间质细胞中ANP依赖性睾酮的产生几乎是两拷贝野生型对照小鼠的两倍（561+/-18 vs. 325+/-11 ng/l x10（6）cells; P < 0.001）。随着Npr 1基因拷贝数的增加，间质细胞中ANP依赖性鸟苷酸环化酶的激活和cGMP的产生逐渐增加。我们的研究结果建立了睾丸类固醇生成的替代机制，除了通过cAMP途径介导的促性腺激素外，还通过NPRA依赖性cGMP信号刺激睾丸类固醇生成。这些发现表明Npr 1基因功能在维持血清睾酮水平和睾丸类固醇生成中的作用，并提供了与NPRA降低和低睾酮水平相关的高血压之间的遗传联系。
Mice lacking the gene (Npr1) encoding the natriuretic peptide receptor A (NPRA) have hypertension with elevated blood pressure and cardiac hypertrophy. In particular, Npr1 gene-deficient male mice exhibit lethal vascular events similar to those seen in untreated human hypertensive patients. Serum testosterone levels tend to be lower in hypertensive male humans than in normal males without hypertension, but the genetic basis for this tendency remains unknown. To determine whether Npr1 gene function affects the testosterone level, we measured serum testosterone in male hypertensive mice lacking a functional Npr1 gene, wild-type animals with two copies, and the gene-duplicated littermates expressing four copies of the gene. In the Npr1 gene-knockout (zero-copy) mice, the serum testosterone level was 62% lower than that in the two-copy control mice (80+/-10 ts. 120+/-14 ng/ml, respectively; P < 0.005). Serum testosterone in the four-copy mice was 144% (P < 0.005) of that in the two-copy wild-type control mice. To investigate the role of NPRA in testicular steroidogenesis, we analyzed atrial natriuretic peptide (ANP)-dependent guanylyl cyclase activation, accumulation of intracellular cGMP, and testosterone production in purified primary Leydig cells from animals with zero, two, or four copies of the Npr1 gene. Leydig cells lacking the Npr1 gene did not show ANP-stimulated guanylyl cyclase activation or cGMP accumulation and had no ANP-dependent testosterone production. ANP stimulation of Leydig cells from the four-copy males elicited a 2-fold greater production of cGMP compared to that in the two-copy wild-type counterparts (260+/-12 vs. 126+/-7 pmol/l x 10(6) cells; P < 0.001). Similarly, ANP-dependent testosterone production in Leydig cells was nearly twice as high in four-copy mice as in two-copy wild-type controls (561+/-18 vs. 325+/-11 ng/l x 10(6) cells; P < 0.001). ANP-dependent guanylyl cyclase activation and production of cGMP in Leydig cells increased progressively with the number of Npr1 gene copies. Our results establish the existence of an alternate mechanism for testicular steroidogenesis that is stimulated by NPRA-dependent cGMP signaling, in addition to that mediated by gonadotropins, via a cAMP pathway. These findings demonstrate the role of Npr1 gene function in the maintenance of serum testosterone levels and testicular steroidogenesis and provide a genetic link between hypertension associated with decreased NPRA and low testosterone levels.