Variable transcriptional regulation of the human aldosterone synthase gene causes salt-dependent high blood pressure in transgenic mice.
Variable transcriptional regulation of the human aldosterone synthase gene causes salt-dependent high blood pressure in transgenic mice.
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DOI：
10.1161/circgenetics.114.000694
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发表时间：
2015-02
期刊：
影响因子：
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通讯作者：
Kumar A
中科院分区：
文献类型：
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作者：
Mopidevi B;Kaw MK;Puri N;Ponnala M;Jain S;Rana A;Keetha NR;Khuder SA;Fiering SN;Kumar A
醛固酮由酶CYP 11B 2在肾上腺皮质中合成，诱导正钠平衡并易患高血压。许多研究者使用基因组DNA分析，将hCYP 11 B2基因的− 344 T多态性与人类高血压联系起来。人类CYP 11B 2基因启动子有三个连锁不平衡的SNP：T/A在-663，T/C在-470和C/T在-344。变体ACT一起出现并形成单倍型-I，而变体TTC构成单倍型-II。我们假设，这些SNPs，当一起存在时，将导致单倍型依赖性差异的转录调控的hCYP 11 B2基因，并影响血压调节。我们评估了组织表达的差异，在体内，和相应的影响，血压源于两个单倍型。在研究中使用具有hCYP 11B 2基因的新型转基因（TG）小鼠，靶向小鼠HPRT基因座，具有单倍型II或I变体。我们的研究结果表明，增加肾上腺和肾脏的hCYP 11B 2的表达在TG小鼠与单倍型-I，与单倍型-II的小鼠相比。重要的是，我们观察到单倍型-I TG小鼠的基线血压升高，高盐饮食加重了这种影响。我们的研究结果证实了醛固酮升高的病理生理影响，显示单倍型I的TG小鼠肾组织中促炎标志物上调。这些发现表征了hCYP 11B 2基因的单体型依赖性调节，其中− 344 T作为报告基因多态性，并表明单体型I导致hCYP 11B 2表达增加，对血压和炎症环境具有容许效应。
Aldosterone, synthesized in the adrenal cortex by the enzyme CYP11B2, induces positive sodium balance and predisposes to hypertension. Various investigators, using genomic DNA analyses, have linked −344T polymorphism in the hCYP11B2 gene to human hypertension. Human CYP11B2 gene promoter has three SNPs in linkage disequilibrium: T/A at −663, T/C at −470 and C/T at −344. Variants ACT occur together and form the haplotype-I while variants TTC constitute haplotype-II. We hypothesize that these SNPs, when present together, will lead to haplotype-dependent differences in the transcriptional regulation of the hCYP11B2 gene and affect blood pressure regulation. We evaluated differences in tissue expression, in vivo, and consequential effects on blood pressure stemming from the two haplotypes. Novel transgenic (TG) mice with the hCYP11B2 gene, targeted to the mouse HPRT locus, with either haplotype-II or I variant are used in the study. Our results show increased adrenal and renal expression of hCYP11B2 in TG mice with haplotype-I, as compared to mice with haplotype-II. Importantly, we observed increased baseline blood pressure in haplotype-I TG mice, an effect accentuated by a high-salt diet. Pathophysiological impact of elevated aldosterone was corroborated by our results showing up-regulation of proinflammatory markers in renal tissues from the TG mice with haplotype-I. These findings characterize haplotype-dependent regulation of the hCYP11B2 gene where −344T serves as a reporter polymorphism and show that haplotype-I leads to increased expression of hCYP11B2, with permissive effects on blood pressure and inflammatory milieu.