MOTS‑c protects against placental injury via Nrf2 activation in hypoxia‑induced intrauterine growth restriction mice.

Intrauterine growth restriction (IUGR) is a leading cause of perinatal morbidity and mortality. Oxidative stress is a key factor in the pathogenesis of IUGR. The transcription factor nuclear factor erythroid 2‑related factor 2 (Nrf2) is a key regulator of the cellular antioxidant response. MOTS‑c, a 16‑amino acid peptide derived from the mitochondria, regulates oxidative stress related pathways. However, the effects of MOTS‑c on IUGR remain unclear. The present study aimed to investigate the role of MOTS‑c in hypoxia‑induced placental restriction and IUGR and its underlying mechanisms. Wild‑type and Nrf2 knockout (KO) maternal mice were exposed to hypoxia from gestational days 11 to 17.5 to establish the IUGR model. Human umbilical vein endothelial cells (HUVECs) were used for in vitro assays. Maternal serum and placenta MOTS‑c concentration were measured using an enzyme‑linked immunosorbent assay. Hematoxylin and eosin staining, reverse transcription‑quantitative PCR, western blotting, immunohistochemistry and immunofluorescence techniques were employed to evaluate the effects of MOTS‑c treatment on IUGR. It was found that reduced placental content of MOTS‑c was positively correlated with low fetal weight in mice with hypoxia‑induced IUGR. The administration of MOTS‑c (5 mg/kg) significantly attenuated hypoxia‑induced IUGR by promoting placental angiogenesis and inhibiting oxidative stress‑mediated placental dysfunction. Furthermore, these protective effects exerted by MOTS‑c were dependent on Nrf2 activation, as administration of MOTS‑c had no protective role in Nrf2 KO mice or HUVECs pre‑treated with ML385, a Nrf2 inhibitor. Taken together, the present study demonstrated that MOTS‑c mitigated placental injury in hypoxia‑induced IUGR by activation of the Nrf2 signaling pathway, thus potentially identifying a novel therapeutic strategy for hypoxia‑induced IUGR.