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

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.

Human kidney organoids produce functional renin

“…Even though an increase in AGT mRNA was observed in the organoids, AGT protein was not detected in the supernatants. A recent publication demonstrated that liver-targeted AGT siRNA decreases AGT and angiotensin I protein levels in the kidney without affecting renal AGT mRNA expression 24 . Renal angiotensin generation is therefore considered to depend on the uptake of hepatic angiotensinogen.…”

Novel Therapeutic Approaches Targeting the Renin-Angiotensin System and Associated Peptides in Hypertension and Heart Failure

“…In rats, both GalNAc-conjugated and unconjugated angiotensinogen ASO suppressed circulating angiotensinogen, although only the unconjugated ASO additionally suppressed renal and adipose angiotensinogen mRNA. Nevertheless, both the GalNAc-conjugated ASO and siRNA effectively lowered blood pressure in SHRs (Mullick et al, 2017; Uijl et al, 2019), suggesting that interference with renal or adipose angiotensinogen is not required for this effect. This was also true for lipid nanoparticle-encapsulated angiotensinogen siRNA delivered to the liver in SHRs (Olearczyk et al, 2014).…”

The emerging role of angiotensinogen in cardiovascular diseases

“…Expectedly, either ASO or RNA-based therapies targeting AGT exerts similar effects as classical blockers of RAS (ACEI or ARB) on cardiac hypertrophy. It has been demonstrated that rats injected with liver-specific AGT siRNA or AAV AGT shRNA exhibit a profound reduction of ratio of heart weight to body weight (Kimura et al, 2001;Uijl et al, 2019).…”