Four-week inhibition of the renin-angiotensin system in spontaneously hypertensive rats results in persistently lower blood pressure with reduced kidney renin and changes in expression of relevant gene networks

Sean G Byars; Priscilla Prestes; Vara Suphapimol; Fumihiko Takeuchi; Nathan De Vries; Michelle C Maier; Mariana Melo; David Balding; Nilesh Samani; Andrew M Allen; Norihiro Kato; Jennifer L Wilkinson-Berka; Fadi Charchar; Stephen B Harrap

doi:10.1093/cvr/cvae053

Four-week inhibition of the renin-angiotensin system in spontaneously hypertensive rats results in persistently lower blood pressure with reduced kidney renin and changes in expression of relevant gene networks

Cardiovasc Res. 2024 Mar 19:cvae053. doi: 10.1093/cvr/cvae053. Online ahead of print.

Affiliations

¹ The Florey Institute of Neuroscience & Mental Health, Parkville, Victoria, Australia.
² Health Innovation and Transformation Centre, Federation University, Ballarat, Victoria, Australia.
³ Department of Anatomy & Physiology, School of Biomedical Sciences, University of Melbourne, Victoria, Australia.
⁴ Department of Gene Diagnostics and Therapeutics, National Center for Global Health and Medicine, Tokyo, Japan.
⁵ Melbourne Integrative Genomic and School of Mathematics & Statistics, University of Melbourne, Victoria, Australia.
⁶ Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

PMID: 38501595
DOI: 10.1093/cvr/cvae053

Abstract

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.