PPAR-γ alleviates preeclampsia-associated placental oxidative stress with involvement of the PI3K/Akt signaling pathway.

Background

Preeclampsia (PE) is characterized by placental dysfunction and oxidative stress. This study investigated whether peroxisome proliferator-activated receptor-γ (PPAR-γ) protects against PE through the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway.

Methods

GSE10588 was analyzed using differential expression, single-sample gene set enrichment analysis, CIBERSORT, and weighted gene co-expression network analysis. PPAR-γ expression was examined in placentas from six patients with PE and six healthy pregnant women. Lipopolysaccharide-treated HTR-8/SVneo cells and N-nitro-L-arginine methyl ester-induced PE rats were used as experimental models. PPAR-γ was modulated by overexpression or rosiglitazone, while PI3K was inhibited with LY294002. Trophoblast function, oxidative stress, maternal blood pressure, proteinuria, placental injury, and PI3K/Akt signaling were evaluated.

Results

PPAR-γ expression correlated positively with oxidative phosphorylation and PI3K/Akt pathway activity and was associated with altered placental immune-cell profiles. PPAR-γ expression was reduced in PE placentas. PPAR-γ overexpression increased trophoblast viability and invasion, reduced apoptosis, and restored antioxidant enzyme activities after lipopolysaccharide exposure. These effects were accompanied by increased PI3K and Akt phosphorylation and were attenuated by LY294002. In L-NAME-treated rats, rosiglitazone improved hypertension, proteinuria, placental injury, and antioxidant enzyme activities, accompanied by increased PI3K and Akt phosphorylation.

Conclusion

PPAR-γ activation alleviates trophoblast dysfunction and placental oxidative injury in PE, at least partly through PI3K/Akt signaling, and may represent a potential therapeutic target.