Key result
Early RAS inhibition with losartan in spontaneously hypertensive rats persistently reduced kidney Ren expression by 23% and lowered mean arterial pressure at 20 weeks of age.
Why the study?
Brief treatment with renin-angiotensin system inhibitors permanently reduces genetic hypertension in spontaneously hypertensive rats, but the relevant renal genetic changes involved in this reprogramming are unknown.
Does brief early inhibition of the renin-angiotensin system with losartan or perindopril reduce kidney renin expression and blood pressure in spontaneously hypertensive rats?
Does brief early inhibition of the renin-angiotensin system with losartan or perindopril reduce kidney renin expression and blood pressure in spontaneously hypertensive rats?
Effect estimate: 23% reduction
p-value: p=0.03
Early, brief renin-angiotensin system inhibition in spontaneously hypertensive rats reprograms genetic pathways, leading to persistently reduced kidney renin expression and lower blood pressure.
Early RAS inhibition may reset renal gene networks with lasting BP effects in SHR; leaves open translation to human hypertension prevention.
BACKGROUND 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 reprogramming, but relevant genetic changes 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). At 20 weeks, six weeks after treatment cessation, mean arterial pressure remained lower in the treated SHR (P = 0.006), kidney Ren expression was reduced by 23% (P = 0.03) and DNA methylation within the Ren promoter region was increased (P = 0.04). Experiments with the ACE inhibitor perindopril confirmed a long-term reduction in kidney Ren expression 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 decreased Ren expression and lower BP. Gene ontogeny analyses revealed that these networks were enriched with genes relevant to BP, RAS and the kidneys. CONCLUSIONS Early RAS inhibition in SHR reprograms genetic pathways and networks resulting in a legacy of reduced Ren expression and the persistent reduction in BP.
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Byars et al. (2023) studied Hypertension (n=57). Losartan vs. Vehicle (saline) or Hydralazine was evaluated on Kidney Ren expression at 20 weeks (6 weeks after treatment cessation) (23% reduction, p=0.03). Early RAS inhibition with losartan in spontaneously hypertensive rats persistently reduced kidney Ren expression by 23% and lowered mean arterial pressure at 20 weeks of age.
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