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 mmHg), followed by captopril+valsartan (−54±4 mmHg), captopril (−23±2 mmHg), siRNA (−14±2 mmHg), and valsartan (−10±2 mmHg). 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.

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Keywords acute kidney injury ◼ hypertrophy, left ventricular ◼ hypertension ◼ renin-angiotensin system ◼ RNA, small interfering ◼ RNAi therapeutics
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Journal Hypertension
Uijl, E, Colafella, K.M.M, Sun, Y, Ren, L, van Veghel, R, Garrelds, I.M, … Danser, A.H.J. (2019). Strong and Sustained Antihypertensive Effect of Small Interfering RNA Targeting Liver Angiotensinogen. Hypertension, 73(6), 1249–1257. doi:10.1161/hypertensionaha.119.12703