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RNA interference therapeutics targeting angiotensinogen ameliorate preeclamptic phenotype in rodent models
- Source :
- J Clin Invest
- Publication Year :
- 2020
- Publisher :
- American Society for Clinical Investigation, 2020.
-
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.
- Subjects :
- 0301 basic medicine
Angiotensin receptor
medicine.medical_specialty
Medizin
Angiotensinogen
Intrauterine growth restriction
Systemic inflammation
Preeclampsia
Rats, Sprague-Dawley
03 medical and health sciences
0302 clinical medicine
Pre-Eclampsia
Pregnancy
Internal medicine
medicine
Animals
Fetus
Proteinuria
business.industry
General Medicine
medicine.disease
Rats
Disease Models, Animal
030104 developmental biology
Endocrinology
Blood pressure
Cardiovascular and Metabolic Diseases
030220 oncology & carcinogenesis
Female
RNA Interference
Rats, Transgenic
medicine.symptom
business
Reperfusion injury
Research Article
Subjects
Details
- ISSN :
- 15588238 and 00219738
- Volume :
- 130
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....d22f12c415e98912c0b0012c7a02daa8