# NRF1 and NRF2 Expression in Preeclamptic Placentas: A Comparative Observational Study

## TL;DR

This study compares NRF1 and NRF2 expression in placentas from preeclamptic pregnancies and healthy controls to understand their role in oxidative stress and inflammation.

## Contribution

The study reveals distinct expression patterns of NRF1 and NRF2 in preeclamptic placentas, linking them to specific metabolic and inflammatory pathways.

## Key findings

- NRF1 expression was significantly decreased in preeclamptic placentas, especially in syncytial knots and fibrinoid areas.
- NRF2 expression was significantly increased in preeclamptic placentas, particularly in syncytiotrophoblasts and stromal cells.
- Decreased NRF1 was linked to glutathione metabolism and AMPK signaling, while increased NRF2 was associated with inflammatory pathways.

## Abstract

Background: Preeclampsia (PE) is a hypertensive disorder of pregnancy associated with oxidative stress and mitochondrial dysfunction. NRF1 and NRF2 are transcription factors that regulate mitochondrial activity and antioxidant defense. This study investigated their expression patterns in placentas from preeclamptic and severe preeclamptic pregnancies by immunohistochemical and bioinformatical methods. Methods: Placentas from 40 healthy controls, 40 PE, and 40 sPE patients were analyzed by histological and immunohistochemical techniques. Protein–protein interaction networks for NRF1, NRF2, and PE-related proteins were constructed using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and Cytoscape software, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis performed via ShinyGO, with significance set at false discovery rate (FDR) < 0.05. Results: NRF1 expression was significantly decreased in PE and sPE groups compared to controls, with notably negative staining in syncytial knots and fibrinoid areas. Conversely, NRF2 expression significantly increased, showing intense positivity in syncytiotrophoblasts, stromal cells, and vascular structures. Pathway analysis revealed that decreased NRF1 expression was associated with glutathione metabolism, hypoxia inducible factor-1 (HIF-1) signaling, and AMP-Activated Protein Kinase (AMPK) signaling pathways. Increased NRF2 expression was associated predominantly with inflammatory and immune response pathways, including AGE-RAGE signaling and pathogen–response pathways. Conclusions: Differential expressions of NRF1 and NRF2 in preeclamptic placentas reflect distinct yet interconnected responses to oxidative stress and inflammation. These transcription factors have potential clinical relevance as biomarkers for PE severity assessment and as targets for future therapeutic interventions.