Role of NRF2 and HO-1 in preeclampsia: polymorphisms, circulating factors and in vitro assays

Abstract

Preeclampsia is the leading cause of mortality and morbidity among pregnant women in Brazil and several countries. Its pathophysiology is complex and involves several processes, including the oxidative stress (increase of free radicals and/or decrease of antioxidant defense). Although evidences, clinical supplementation with vitamins (C and E) was not promising in preeclampsia. Currently, therapeutically the activation of transcription factor, NRF2 (nuclear factor, erythroid 2-like 2), has been explored in several diseases. This factor promote cytoprotection by activates the transcription of several antioxidant and detoxification proteins. Hemeoxigenase-1 (HO-1) is the most studied, because has antiapoptotic, anti-inflammatory and cytoprotection activities. Until now, only two studies have been performed in preeclampsia, using placenta or cytotrophoblast. Therefore, the aims of current project are compare among healthy pregnant and preeclampsia pregnant (responsive or nonresponsive to antihypertensive therapy) the frequencies of polymorphisms located in gene which encodes NRF2 and HO-1, the plasma levels of HO-1 and the antioxidant activity of plasma. Besides we will perform several studies in vitro incubating plasma with endothelial cell cultures and verify: NRF2 and HO-1 gene and protein expressions, NRF2 translocation, we will validate the NRF2 effects using siRNA against NRF2, and we will evaluate the microRNAs expressions which regulate NRF2. Also, cell viability and apoptosis will be evaluated here. Finally, aiming to improve preeclampsia therapy, we will use resveratrol (present in high quantities in grapes), an inductor of NRF2, in these cultures, and again all cells parameters will be evaluated. We believe that the data obtained in this project will provide relevant information to the study and therapy of preeclampsia in the global context. (AU)