Metformin attenuates placental oxidative stress through Nrf2/Keap1 signaling in preeclampsia rats
Abstract
BACKGROUND: 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.
METHODS: 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.
RESULTS: Significant reductions in systolic…
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