RNA interference therapeutics targeting angiotensinogen ameliorate preeclamptic phenotype in rodent models

Nadine Haase, Donald J. Foster, Mark W. Cunningham, Julia Bercher, Tuyen Nguyen, Svetlana Shulga-Morskaya, Stuart Milstein, Sarfraz Shaikh, Jeff Rollins, Michaela Golic, Florian Herse, Kristin Kräker, Ivo Bendix, Meray Serdar, Hanna Napieczynska, Arnd Heuser, Alexandra Gellhaus, Kristin Thiele, Gerd Wallukat, Dominik N. MüllerBabbette LaMarca, Ralf Dechend

Research output: Contribution to journalArticlepeer-review

Abstract

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 midgestation (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.

Original languageEnglish
Pages (from-to)2928-2942
Number of pages15
JournalJournal of Clinical Investigation
Volume130
Issue number6
DOIs
StatePublished - 1 Jun 2020

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