TY - JOUR
T1 - RNA interference therapeutics targeting angiotensinogen ameliorate preeclamptic phenotype in rodent models
AU - Haase, Nadine
AU - Foster, Donald J.
AU - Cunningham, Mark W.
AU - Bercher, Julia
AU - Nguyen, Tuyen
AU - Shulga-Morskaya, Svetlana
AU - Milstein, Stuart
AU - Shaikh, Sarfraz
AU - Rollins, Jeff
AU - Golic, Michaela
AU - Herse, Florian
AU - Kräker, Kristin
AU - Bendix, Ivo
AU - Serdar, Meray
AU - Napieczynska, Hanna
AU - Heuser, Arnd
AU - Gellhaus, Alexandra
AU - Thiele, Kristin
AU - Wallukat, Gerd
AU - Müller, Dominik N.
AU - LaMarca, Babbette
AU - Dechend, Ralf
N1 - Funding Information:
This work was supported by Alnylam Pharmaceuticals (Cambridge, Massachusetts, USA). We thank Jutta Meisel, Astrid Schiche, Juliane Anders, and Ute Gerhard for their excellent technical assistance.
Publisher Copyright:
© 2020, American Society for Clinical Investigation.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85085855390&partnerID=8YFLogxK
U2 - 10.1172/JCI99417
DO - 10.1172/JCI99417
M3 - Article
C2 - 32338644
AN - SCOPUS:85085855390
SN - 0021-9738
VL - 130
SP - 2928
EP - 2942
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 6
ER -