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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.

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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.
Division of Nephrology and Transplantation (E.U., E.J.H.), Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
Cardiovascular Program, Biomedicine Discovery Institute and Department of Physiology, Monash University, Melbourne, VIC, Australia (K.M.M.C.).
Attoquant Diagnostics, Vienna, Austria (M.P.).
Alnylam Pharmaceuticals, Cambridge, MA (I.Z., J.B.K., D.F.).


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.


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

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