Aims Prevention of human hypertension is an important challenge and has been achieved in experimental models. Brief treatment with renin-angiotensin system (RAS) inhibitors permanently reduces the genetic hypertension of the spontaneously hypertensive rat (SHR). The kidney is involved in this fascinating phenomenon, but relevant changes in gene expression are unknown. Methods In SHR, we studied the effect of treatment between 10 and 14 weeks of age with the angiotensin receptor blocker, losartan, or the angiotensin-converting enzyme (ACE) inhibitor, perindopril (with controls for non-specific effects of lowering BP) on differential RNA expression, DNA methylation and renin immunolabelling in the kidney at 20 weeks of age. Results RNA sequencing revealed a 6-fold increase in renin gene (Ren) expression during losartan treatment (P < 0.0001). Six weeks after losartan, arterial pressure remained lower (P = 0.006), yet kidney Ren showed reduced expression by 23% after losartan (P = 0.03) and by 43% after perindopril (P = 1.4 x 10-6) associated with increased DNA methylation (P = 0.04). Immunolabelling confirmed reduced cortical renin after earlier RAS blockade (P = 0.002). RNA sequencing identified differential expression of mRNAs, miRNAs and lncRNAs with evidence of networking and co-regulation. These included 13 candidate genes (Grhl1, Ammecr1l, Hs6st1, Nfil3, Fam221a, Lmo4, Adamts1, Cish, Hif3a, Bcl6, Rad54l2, Adap1, Dok4), the miRNA miR-145-3p and the lncRNA AC115371. Gene ontogeny analyses revealed that these networks were enriched with genes relevant to BP, RAS and the kidneys. Conclusions Early RAS inhibition in SHR resets genetic pathways and networks resulting in a legacy of reduced Ren expression and BP persisting for a minimum of 6 weeks.

中文翻译：

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对自发性高血压大鼠的肾素-血管紧张素系统进行为期 4 周的抑制可导致血压持续降低，同时肾素减少以及相关基因网络表达的变化

目的 预防人类高血压是一项重要挑战，并已在实验模型中实现。使用肾素-血管紧张素系统（RAS）抑制剂进行短暂治疗可永久降低自发性高血压大鼠（SHR）的遗传性高血压。肾脏参与了这一令人着迷的现象，但基因表达的相关变化尚不清楚。方法 在 SHR 中，我们研究了 10 至 14 周龄时使用血管紧张素受体阻滞剂氯沙坦或血管紧张素转换酶 (ACE) 抑制剂培哚普利（以降低血压的非特异性作用作为对照）治疗的效果。 20周龄肾脏中的差异RNA表达、DNA甲基化和肾素免疫标记。结果 RNA 测序显示，氯沙坦治疗期间肾素基因 (Ren) 表达增加了 6 倍（P < 0.0001）。氯沙坦治疗六周后，动脉压仍然较低 (P = 0.006)，但氯沙坦治疗后肾 Ren 表达减少 23% (P = 0.03)，培哚普利治疗后减少 43% (P = 1.4 x 10-6)，且与 DNA 增加相关甲基化（P = 0.04）。免疫标记证实早期 RAS 阻断后皮质肾素减少 (P = 0.002)。 RNA 测序鉴定了 mRNA、miRNA 和 lncRNA 的差异表达，并具有网络和共同调节的证据。其中包括 13 个候选基因（Grhl1、Ammecr1l、Hs6st1、Nfil3、Fam221a、Lmo4、Adamts1、Cish、Hif3a、Bcl6、Rad54l2、Adap1、Dok4）、miRNA miR-145-3p 和 lncRNA AC115371。基因个体发育分析表明，这些网络富含与 BP、RAS 和肾脏相关的基因。结论 SHR 中的早期 RAS 抑制会重置遗传途径和网络，导致 Ren 表达减少和 BP 持续至少 6 周。