DIABETIC EMBRYOPATHY: ADDRESSING THE EFFECT OF A MITOCHONDRIAL ANTIOXIDANT

HIGA R, ROBERTI S, MAZZUCCO MB, WHITE V, JAWERBAUM A

Congreso; 47TH Annual Meeting of the Diabetes and Pregnancy Study Group of EASD; 2015

A pro-oxidant intrauterine environment has been involved in the embryo damage induced by maternal diabetes even in mild experimental models of this metabolic disease. The mitochondrion is the main source of reactive oxygen species in different tissues. Aiming to address whether mitochondrial-induced oxidative stress is involved in diabetic embryopathy, we analyzed the effect of maternal treatments with idebenone (a mitochondrial antioxidant) in pro-oxidant and pro-inflammatory pathways on E10.5 embryos from control and mild diabetic rats. A pregestational model of mild diabetes was induced by neonatal streptozotocin administration (90 mg/dl). Maternal treatments with idebenone (100 mg/kg, oral treatment) or vehicle (water) were performed from day 1 to 10.5 of gestation. Embryos were explanted and preserved for the evaluation of the expression of genes involved in redox balance (NRF2, MnSOD), in the pro-inflammatory state(TNFalpha) and in mitochondrial biogenesis and function (NRF1, PGC-1alpha). In addition, protein expression of the mitochondrial protein COX-IV was immunolocalized, peroxynitrite-induced damage was evaluated by anti-nitrotyrosine immunostaining and PARP was immunolocalized as a marker of apoptotic pathways. We found that NRF2 expression was increased in embryos from diabetic rats and decreased when the diabetic rats were treated with idebenone (p lower than 0.05). NRF1 and PGC1alpha expression, which were decreased in embryos from diabetic rats, were upregulated when the rats were treated with idebenone (p lower than 0.05). Although TNFalpha and MnSOD expression were increased in embryos from diabetic rats, there were no changes with the idebenone treatments. The increases in peroxynitrite-induced damage and PARP protein expression that were evidenced in embryos from diabetic rats were prevented by maternal treatments with idebenone. This treatment also upregulated the protein expression of the mitochondrial marker COX-IV. Our results suggest that diabetes-induced oxidative stress in the embryo is highly related to the mitochondrial function, as a mitochondrial antioxidant was effective in the regulation of genes that control the antioxidant response, in the mitochondrial function/biogenesis and in the prevention of cellular damage in this susceptible period of embryo development.