Genetic reprogramming by brief inhibition of the renin-angiotensin system in spontaneously hypertensive rats leads to persistently reduced kidney renin and low blood pressure

Abstract

ABSTRACTBACKGROUNDPrevention 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 reprogramming, but relevant genetic changes are unknown.METHODSIn 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.RESULTSRNA sequencing revealed a 6-fold increase in renin gene (Ren) expression during losartan treatment (P < 0.0001). At 20 weeks, six weeks after treatment cessation, mean arterial pressure remained lower in the treated SHR (P = 0.006), kidneyRenexpression was reduced by 23% (P = 0.03) and DNA methylation within theRenpromoter region was increased (P = 0.04). Experiments with the ACE inhibitor perindopril confirmed a long-term reduction in kidneyRenexpression of 43% (P = 1.4 x 10-6). Renin immunolabelling was also lower after losartan or perindopril treatment (P = 0.002). RNA sequencing identified differential expression of 13 candidate genes (Grhl1,Ammecr1l,Hs6st1,Nfil3,Fam221a,Lmo4,Adamts1,Cish,Hif3a,Bcl6,Rad54l2,Adap1,Dok4) and the miRNA miR-145-3p. We found correlations between expression of mRNAs, miRNAs and lncRNAs that we believe represent genetic networks underpinning the decreasedRenexpression and lower BP. Gene ontogeny analyses revealed that these networks were enriched with genes relevant to BP, RAS and the kidneys.CONCLUSIONSEarly RAS inhibition in SHR reprograms genetic pathways and networks resulting in a legacy of reducedRenexpression and the persistent reduction in BP.