Geburtshilfe Frauenheilkd 2013; 73(12): 1236-1240
DOI: 10.1055/s-0033-1360133
Review
GebFra Science
Georg Thieme Verlag KG Stuttgart · New York

New Insights into the Pathogenesis of Preeclampsia – The Role of Nrf2 Activators and their Potential Therapeutic Impact

Neue Einblicke in der Pathogenese der Präeklampsie – die Rolle von Nrf2-Aktivatoren und ihre potenzielle therapeutische Wirkung
N. Kweider
1   Medical Faculty, RWTH Aachen University, Department of Anatomy and Cell Biology, Aachen
,
C. J. Wruck
1   Medical Faculty, RWTH Aachen University, Department of Anatomy and Cell Biology, Aachen
,
W. Rath
2   Medical Faculty, RWTH Aachen University, Obstetrics and Gynecology, Aachen
› Author Affiliations
Further Information

Publication History

received 05 August 2013
revised 25 October 2013

accepted 06 November 2013

Publication Date:
20 December 2013 (online)

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Abstract

Preeclampsia (PE), characterized by proteinuric hypertension and occurring in 2–3 % of all pregnancies, is one of the leading causes of maternal, fetal and neonatal morbidity and mortality. The etiology of PE still remains unclear and current treatments for this devastating disorder are still limited to symptomatic therapies. Placental oxidative stress may be a key intermediate step in the pathogenesis of PE; it has been related to excessive secretion of multiple antiangiogenic factors, mainly soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). The nuclear factor-erythroid 2-like 2 (Nrf2) pathway is one of the most important systems that enhance cellular protection against oxidative stress. Nrf2 serves as a master transcriptional regulator of the basal and inducible expression of a multitude of genes encoding detoxification enzymes and antioxidative proteins. Evidence for a link between Nrf2 and restoring the balance between pro- and antiangiogenic factors mainly through its downstream target protein heme oxygenase-1 (HO-1) has lately been discussed. HO-1 metabolizes heme to biliverdin, iron and carbon monoxide (CO). CO enhances vascular endothelial growth factor (VEGF) synthesis in vascular smooth muscle and promotes its relaxation and hence vasodilatation. In addition, HO-1 has been shown in vitro to inhibit the production of sFlt-1. A recent animal study demonstrated that the induction of HO-1 in a mouse model of PE attenuates the induced hypertension in pregnant mice. This provides compelling evidence for the protective role of Nrf2/HO-1 in pregnancy and identifies this pathway as a target to treat women with PE. We summarize the recent findings on the involvement of Nrf2 in the pathogenesis of PE, and provide an overview of the possible beneficial effects of Nrf2 inducers in PE.

Zusammenfassung

Präeklampsie (PE) ist charakterisiert durch Gestationshypertonie und Proteinurie; mit einer Prävalenz von 2 bis 3 % zählt sie zu den häufigsten Schwangerschaftserkrankungen. Präeklampsie gehört zu den führenden Ursachen für fetale, neonatale und mütterliche Morbidität und Mortalität. Die Ätiologie dieses Syndroms ist noch unbekannt, und die Behandlung richtet sich daher nach den Symptomen. Studien haben gezeigt, dass oxidativer Stress in der Plazenta eine wichtige Rolle bei der Pathogenese der Präeklampsie spielen könnte. Plazentaler oxidativer Stress könnte zu einer erhöhten Freisetzung von antiangiogenetischen Faktoren wie fms-like Tyrosine Kinase-1 (sFlt-1) und Soluble Endoglin (sEng) führen. Der Nuclear-Factor-Erythroid-like-2-(Nrf2-)Signalweg ist ein wichtiges System, das die Zellen vor oxidativen Stress schützt. Die Expression vieler antioxidativer Enzyme wird von Nrf2 verstärkt. Es wurde ferner berichtet, dass das Nrf2-System eine Rolle bei der Regulierung der Balance von pro- und antiangiogenen Faktoren spielt, indem es das Zielprotein Hämoxygenase-1 (HO-1) hochreguliert. HO-1 katalysiert die Oxidation von Häm zu Biliverdin, Eisen und Kohlenmonoxide (CO). CO stimuliert die Proteinsynthese des vaskulären endothelialen Wachstumsfaktors VEGF in vaskulären glatten Muskelzellen, und kann auch die Relaxation der glatten Muskulatur (Gefäßerweiterung) induzieren. Zudem kann HO-1 in vitro die Freisetzung von sFlt-1 hemmen. Darüber hinaus wurde kürzlich in Studien gezeigt, dass die Aktivierung von HO-1 in verschiedenen Tiermodellen für Präeklampsie zu einer Blutdrucksenkung führt. Diese Studien zeigen, dass der Nrf2/HO-1 Signalweg eine präventive Rolle bei Präeklampsie spielen könnte. Ziel dieser Übersichtsarbeit ist es, die neuesten wissenschaftlichen Studien zur Beteiligung von Nrf2 an der Pathogenese von Präeklampsie zusammenzufassen. Zudem möchten wir einen Überblick über das therapeutische Potenzial von Nrf2-Aktivatoren bei der Präeklampsie geben.

Key words

preeclampsia - Nrf2 - heme oxygenase-1

Schlüsselwörter

Präeklampsie - Nrf2 - Hämoxygenase-1
 

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