부산대학교 도서관

Introduction: Preeclampsia, syndrome with hallmark features of new-onset hypertension and proteinuria after 20 weeks of gestation, affects 5% of pregnancies. It is a major cause of fetal and maternal morbidity/mortality. Several genetic studies have demonstrated that dysregulation of Angiotensin II is involved in the pathogenesis of the disease; however, treatment with ACE inhibitor or AT1 receptor blocker is contraindicated due to fetal toxicity.Hypothesis: Investigational RNAi therapeutics are highly potent mediators of gene-specific silencing. We tested angiotensinogen (AGT)-specifc siRNA, conjugated to triantennary GalNAc, for the ability to ameliorate symptoms of preeclampsia in rat models, without inducing a placental pathology or affecting fetal health.Methods: Two rodent models of preeclampsia were used, which reflect different mechanisms inducing the preeclamptic phenotype. The first model (transgenic) acts by upregulation of the circulating and uteroplacental Renin-Angiotensin-System (RAS). The second model is a surgical model that induces ischemia/reperfusion injury and subsequent local and systemic inflammation restriction (RUPP). Beginning on day 3 of gestation, transgenic rats were dosed s.c. with 10 mg/kg siRNA every third day through gestation day 15. In RUPP rats, siRNA was s.c. injected once (10mg/kg) on day 12 of gestation.Results: The major finding is that RNAi therapeutics targeting maternal hepatic AGT ameliorated the preeclamptic phenotype in both models. With this technique we were able to selectively reduce maternal RAS signaling, while preserving the fetal RAS. In the transgenic model, silencing of hAGToccurred only in the maternal liver and decreased AGT and angiotensin metabolites in the tissue and circulating RAS, leading to a reduction of blood pressure and urinary albumin excretion. We improved IUGR indicating an improved fetal development. The RUPP model confirmed the findings in a model that is not explicitly driven by the RAS. Critically, fetal weights were not reduced in the treated group, and blood pressure was lowered.Conclusions: Our data show that an RNAi therapeutic targeting AGT ameliorated the clinical sequelae of preeclampsia in a transgenic rat model and improved the outcome of the fetus.