Format

Send to

Choose Destination
Hypertension. 2019 Jun;73(6):1249-1257. doi: 10.1161/HYPERTENSIONAHA.119.12703.

Strong and Sustained Antihypertensive Effect of Small Interfering RNA Targeting Liver Angiotensinogen.

Author information

1
From the Division of Vascular Medicine and Pharmacology (E.U., K.M.M.C., Y.S., L.R., R.v.V., I.M.G., R.d.V., A.H.J.D.), Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
2
Division of Nephrology and Transplantation (E.U., E.J.H.), Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
3
Cardiovascular Program, Biomedicine Discovery Institute and Department of Physiology, Monash University, Melbourne, VIC, Australia (K.M.M.C.).
4
Attoquant Diagnostics, Vienna, Austria (M.P.).
5
Alnylam Pharmaceuticals, Cambridge, MA (I.Z., J.B.K., D.F.).

Abstract

Small interfering RNAs (siRNAs) targeting hepatic angiotensinogen ( Agt) may provide long-lasting antihypertensive effects, but the optimal approach remains unclear. Here, we assessed the efficacy of a novel AGT siRNA in spontaneously hypertensive rats. Rats were treated with vehicle, siRNA (10 mg/kg fortnightly; subcutaneous), valsartan (31 mg/kg per day; oral), captopril (100 mg/kg per day; oral), valsartan+siRNA, or captopril+valsartan for 4 weeks (all groups, n=8). Mean arterial pressure (recorded via radiotelemetry) was lowered the most by valsartan+siRNA (-68±4 mm Hg), followed by captopril+valsartan (-54±4 mm Hg), captopril (-23±2 mm Hg), siRNA (-14±2 mm Hg), and valsartan (-10±2 mm Hg). siRNA and captopril monotherapies improved cardiac hypertrophy equally, but less than the dual therapies, which also lowered NT-proBNP (N-terminal pro-B-type natriuretic peptide). Glomerular filtration rate, urinary NGAL (neutrophil gelatinase-associated lipocalin), and albuminuria were unaffected by treatment. siRNA lowered circulating AGT by 97.9±1.0%, and by 99.8±0.1% in combination with valsartan. Although siRNA greatly reduced renal Ang (angiotensin) I, only valsartan+siRNA suppressed circulating and renal Ang II. This coincided with decreased renal sodium hydrogen exchanger type 3 and phosphorylated sodium chloride cotransporter abundances. Renin and plasma K+ increased with every treatment, but especially during valsartan+siRNA; no effects on aldosterone were observed. Collectively, these data indicate that Ang II elimination requires >99% suppression of circulating AGT. Maximal blockade of the renin-angiotensin system, achieved by valsartan+siRNA, yielded the greatest reduction in blood pressure and cardiac hypertrophy, whereas AGT lowering alone was as effective as conventional renin-angiotensin system inhibitors. Given its stable and sustained efficacy, lasting weeks, RNA interference may offer a unique approach to improving therapy adherence and treating hypertension.

KEYWORDS:

RNA, small interfering; RNAi therapeutics; acute kidney injury; hypertension; hypertrophy, left ventricular; renin-angiotensin system

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center