RNA interference therapeutics targeting angiotensinogen ameliorate preeclamptic phenotype in rodent models

Affiliations

• ¹ Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
• ² Charité - Universitätsmedizin Berlin, Berlin Germany.
• ³ Experimental and Clinical Research Center, Berlin, Germany.
• ⁴ DZHK (German Centre for Cardiovascular Research), Berlin, Germany.
• ⁵ Berlin Institute of Health (BIH), Berlin, Germany.
• ⁶ Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
• ⁷ Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA.
• ⁸ Department of Pediatrics I Neonatology and Experimental Perinatal Neurosciences and.
• ⁹ Department of Gynecology and Obstetrics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
• ¹⁰ Department of Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
• ¹¹ Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, Mississippi, USA.
• ¹² HELIOS-Klinikum, Berlin, Germany.Preeclampsia, with the hallmark features of new-onset hypertension and proteinuria after 20 weeks of gestation, is a major cause of fetal and maternal morbidity and mortality. Studies have demonstrated a role for the renin-angiotensin system (RAS) in its pathogenesis; however, small-molecule RAS blockers are contraindicated because of fetal toxicity. We evaluated whether siRNA targeting maternal hepatic angiotensinogen (Agt, ) could ameliorate symptoms of preeclampsia without adverse placental or fetal effects in 2 rodent models. The first model used a cross of females expressing human Agt, with males expressing human renin, resulting in upregulation of the circulating and uteroplacental RAS. The second model induced ischemia/reperfusion injury and subsequent local and systemic inflammation by surgically reducing placental blood flow mid-gestation (reduced uterine perfusion pressure [RUPP]). These models featured hypertension, proteinuria, and fetal growth restriction, with altered biomarkers. siRNA treatment ameliorated the preeclamptic phenotype in both models, reduced blood pressure, and improved intrauterine growth restriction, with no observed deleterious effects on the fetus. Treatment also improved the angiogenic balance and proteinuria in the transgenic model, and it reduced angiotensin receptor activating antibodies in both. Thus, an RNAi therapeutic targeting Agt, ameliorated the clinical sequelae and improved fetal outcomes in 2 rodent models of preeclampsia.