Transcriptomic Response in the Heart and Kidney to Different Types of Antihypertensive Drug Administration
Transcriptomic Response in the Heart and Kidney to Different Types of Antihypertensive Drug Administration
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DOI：
10.1161/hypertensionaha.121.18026
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发表时间：
2021-12
期刊：
影响因子：
8.3
通讯作者：
F. Takeuchi;Yi-Qiang Liang;M. Isono;M. Ang;Kotaro Mori;N. Kato
中科院分区：
文献类型：
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作者：
F. Takeuchi;Yi-Qiang Liang;M. Isono;M. Ang;Kotaro Mori;N. Kato
补充数字内容可在文本中找到。某些类别的抗高血压药物可能对终末器官损伤（如左心室肥大）产生特异性、非血压（BP）依赖性保护作用，尽管临床试验中的总体证据尚未确定。为了阐明降压药物诱导的基因表达变化（可能与改善终末器官损伤相关），我们对心脏和肾脏进行了体内表型评估和转录组分析，并对两种近交系（即高血压和正常血压）大鼠给予降压药物。我们选择了6种抗高血压药物：依那普利（血管紧张素转换酶抑制剂）、坎地沙坦（血管紧张素受体阻滞剂）、氢氯噻嗪（利尿剂）、卡维地洛（钙通道阻滞剂）、卡维地洛（血管舒张β受体阻滞剂）和肼苯哒嗪。在测试的大鼠品系中，6种药物中的4种，包括2种肾素-血管紧张素系统抑制剂，对降低血压有效，而其余2种药物则无效。除了降低血压外，在表型变化中似乎存在一些药物间异质性，例如体重增加抑制和体重调整的心脏重量降低。对于转录组反应，相当多的基因表现出显着的mRNA表达变化，无论是在BP依赖性或BP独立的方式与靶器官之间的实质性差异。mRNA表达的显著变化特别是由肾素-血管紧张素系统阻断引起的，例如，心脏中的利钠肽系统（Nppb和Corin）中的基因和肾脏中的肾素-血管紧张素系统/激肽释放酶-激肽系统（Ren和大鼠Klk 1旁系同源物）中的基因以及与钙离子结合相关的基因（Calb 1和Slc 8a 1）。这里构建的研究资源将有助于证实临床环境中偶尔不确定的证据。
Supplemental Digital Content is available in the text. Certain classes of antihypertensive drug may exert specific, blood pressure (BP)-independent protective effects on end-organ damages such as left ventricular hypertrophy, although the overall evidence has not been definitive in clinical trials. To unravel antihypertensive drug-induced gene expression changes that are potentially related to the amelioration of end-organ damages, we performed in vivo phenotypic evaluation and transcriptomic analysis on the heart and the kidney, with administration of antihypertensive drugs to two inbred strains (ie, hypertensive and normotensive) of rats. We chose 6 antihypertensive classes: enalapril (angiotensin-converting enzyme inhibitor), candesartan (angiotensin receptor blocker), hydrochlorothiazide (diuretics), amlodipine (calcium-channel blocker), carvedilol (vasodilating β-blocker), and hydralazine. In the tested rat strains, 4 of 6 drugs, including 2 renin-angiotensin system inhibitors, were effective for BP lowering, whereas the remaining 2 drugs were not. Besides BP lowering, there appeared to be some interdrug heterogeneity in phenotypic changes, such as suppressed body weight gain and body weight-adjusted heart weight reduction. For the transcriptomic response, a considerable number of genes showed prominent mRNA expression changes either in a BP-dependent or BP-independent manner with substantial diversity between the target organs. Noticeable changes of mRNA expression were induced particularly by renin-angiotensin system blockade, for example, for genes in the natriuretic peptide system (Nppb and Corin) in the heart and for those in the renin-angiotensin system/kallikrein-kinin system (Ren and rat Klk1 paralogs) and those related to calcium ion binding (Calb1 and Slc8a1) in the kidney. The research resources constructed here will help corroborate occasionally inconclusive evidence in clinical settings.