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RNA interference therapeutics targeting angiotensinogen ameliorate preeclamptic phenotype in rodent models

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Item Type:Article
Title:RNA interference therapeutics targeting angiotensinogen ameliorate preeclamptic phenotype in rodent models
Creators Name:Haase, N. and Foster, D.J. and Cunningham, M.W. and Bercher, J. and Nguyen, T. and Shulga-Morskaya, S. and Milstein, S. and Shaikh, S. and Rollins, J. and Golic, M. and Herse, F. and Kräker, K. and Bendix, I. and Serdar, M. and Napieczynska, H. and Heuser, A. and Gellhaus, A. and Thiele, K. and Wallukat, G. and Müller, D.N. and LaMarca, B. and Dechend, R.
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.
Keywords:Animals, Rats
Source:Journal of Clinical Investigation
ISSN:0021-9738
Publisher:American Society for Clinical Investigation
Volume:130
Number:6
Page Range:2928-2942
Date:1 June 2020
Additional Information:Copyright: © 2020, American Society for Clinical Investigation
Official Publication:https://doi.org/10.1172/JCI99417
PubMed:View item in PubMed

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