Metformin attenuates placental oxidative stress through Nrf2/Keap1 signaling in preeclampsia rats

Preeclampsia (PE) represents a severe gestational disorder defined by the development of hypertension accompanied by systemic organ dysfunction during pregnancy, affecting 3 %-5 % of pregnancies globally and contributing markedly to maternal-perinatal mortality. Placental oxidative stress (OS) is a key pathophysiological driver. A well-known antidiabetic drug metformin (MET) possesses anti-inflammatory and antioxidant properties, suggesting its therapeutic potential for PE; however, its molecular mechanisms remain unclear.

A PE-like rat model was established using N(ω)-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase inhibitor. Pregnant Sprague-Dawley rats (n = 30) were divided into the control, l-NAME, and l-NAME + MET groups. We evaluated clinical parameters (blood pressure, proteinuria, placental, and renal histopathology), angiogenic factors (soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF)), and OS markers (malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT)). Nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch Like ECH Associated Protein 1 (Keap1) signaling analysis employed western blotting, immunohistochemistry, immunofluorescence and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Molecular docking and dynamics simulations explored MET's interaction with the Nrf2-Keap1 complex.

Significant reductions in systolic blood pressure, proteinuria, and placental-renal histopathological damage, along with improved fetal weight, were observed with MET treatment. It normalized the sFlt-1/PlGF ratio and boosted antioxidant enzyme activities. MET promoted nuclear Nrf2 translocation, upregulated NAD(P)H:quinone oxidoreductase 1 (NQO1), and suppressed Keap1. Molecular modeling suggests that MET-induced destabilization of the Nrf2-Keap1 complex facilitates Nrf2 dissociation.

MET mitigates l-NAME induced oxidative stress by activating the Nrf2 signaling pathway, highlighting its potential as a novel therapeutic target for PE management.