Inactivation of Nrf2 Ameliorates Perinatal Complications in Angiotensin II Induced Pregnancy-Associated Hypertension Mice through Enhancing Placental Angiogenesis

Presentation Number: SUN 536
Date of Presentation: April 2nd, 2017

Masahiro Nezu*1, Tomokazu Souma2, Fumitoshi Satoh3, Sadayoshi Ito1, Norio Suzuki2 and Masayuki Yamamoto2
1Tohoku University Hospital, Sendai, Japan, 2Tohoku University Graduate School of Medicine, 3Tohoku University Graduate School of Medicine, Sendai, Japan

Abstract

Preeclampsia is the hypertensive disorder in pregnancy and thought to be a disease of placenta. Activation of the renin-angiotensin system (RAS) in placenta plays an important role in pathogenesis of preeclampsia. RAS activates NADPH oxidase that induces excessive reactive oxygen species (ROS) as oxidative stress. Keap1-Nrf2 system is a critical regulator for cellular anti-oxidative stress response through controlling transcription of antioxidant genes. Although oxidative stress is one of major pathological mechanisms in preeclampsia, the precise mechanism is mostly uncovered. Then we hypothesized that Keap1-Nrf2 system is associated with RAS-induced ROS signaling in preeclampsia by modulating Nrf2 activity. To elucidate the role of Keap1-Nrf2 system on preeclampsia pathology, we generated transgenic mouse models of preeclampsia/pregnancy-associated hypertension (PAH mice), in which angiotensin II is overpoduced selectively in late phase of pregnancy, under different Nrf2 conditions (deficient, normal or activated). First we analyzed the maternal and neonatal outcomes of PAH mice and compared with the normal pregnant (NP) mice. Genetic deletion of Nrf2 rescued the maternal and fetal mortality of PAH mice, as well as intrauterine growth retardation (IUGR). Since the placental vascular development is closely associated with fetal and maternal exchange of oxygen and nutrition, we analyzed the vascular network in placenta in the late stage of pregnancy. Then we found that Nrf2 deficiency ameliorated the vascular network formation that was impaired in PAH mice. The level of oxidative DNA damage in the placental labyrinth zone was inversely correlated with the level of Nrf2 activity. Nrf2-hyperactivated placenta showed severely repressed angiogenesis with negligible oxidative DNA damages. Microarray analysis and RT-PCR analysis showed that gene expressions of the various angiogenic cytokines and chemikines were upregulated in Nrf2-deficient PAH mice Our findings demonstrate that the inhibition of Nrf2 ameliorates perinatal outcomes in the RAS-induced preeclampsia model, and that ROS signaling may be essential for placental angiogenesis in preeclampsia.

 

Nothing to Disclose: MN, TS, FS, SI, NS, MY