Abstract P1106: RND3/rhoe Deficiency Results in Mitochondrial Dysfunction in Placenta With Preeclampsia Through Modulating PPARγ Pathway

Abstract

Preeclampsia (PE) is a life-threaten disease among the pregnant women with the syndromes of severe hypertension, proteinuria and pitting edema. Mitochondrial dysfunction mediated oxidative stress has been implicated in the placentae with PE. However, the regulatory mechanism causing the mitochondrial dysfunction is still unknown. In this study, we identified Rnd3, a small Rho GTPase, as a new factor participating in the regulation of mitochondrial function. 46% and 51% decreases in RND3 expression levels were found in the human placentae with PE and in the primary trophoblasts isolated from PE patients, respectively. The downregulation of RND3 in the human PE primary trophoblasts was associated with excessive ROS generation and damaged mitochondrial integrity. To explore the role of Rnd3 in mitochondria, we knocked down of RND3 in trophoblastic BeWo cells and detected the loss of mitochondria cristae, the generation of mitochondrial dygradosome, the mitochondrial membrane potential depolarization and the 4.9 fold increased proton leak from mitochondrial respiratory chain. The overexpression of GFP-Rnd3, by contrast, attenuated hypoxia induced oxidative stress and apoptosis in BeWo cells. In the mechanistic studies, up-regulation of Rnd3 resulted in the nuclear accumulation of transcription factor PPARγ. By stimulation of PPARγ in BeWo cells, mitochondrial uncoupling protein 1 (UCP1) cascade was activated, and the Rnd3 deficiency mediated mitochondrial proton leak was attenuated. Finally, we performed the adenovirus mediated Rnd3 overexpression in the human PE primary trophoblasts, and detected significant decreases in ROS level and apoptosis. We concluded that Rnd3 acted as a novel protective factor in placental mitochondria through PPARγ-UCP1 signaling promotion. Rnd3 downregulation observed in PE patients may explain one of the pathogeneses of severe placental oxidative stress.