MMP/TIMP DISBALANCE AND NO OVERPRODUCTION IN DIABETIC EMBRYOPATHY ARE AMELIORATED BY MATERNAL TREATMENTS WITH FOLIC ACID.

HIGA R; CAPOBIANCO E; WHITE V; JAWERBAUM A

Varsovia

Congreso; 42th Annual meeting of DPSG; 2010

DPSG, EASG

Maternal diabetes increases the risk of embryo malformations. MMPs are proteolytic enzymes involved in the remodeling of the extracellular matrix during embryo development, capable of being activated by NO. The aim of this work was to evaluate putative alterations in the activity of MMP2 and MMP9, in the levels of TIMPs (the endogenous inhibitors of MMPs) and in NO production in embryos and deciduas from diabetic rats during early organogenesis, and to analyze whether these changes were ameliorated by maternal treatments with folic acid. Diabetes was induced by streptozotocin administration (50 mg/kg) to adult rats before mating. Folate (0.5% s.c.) was administered to control and diabetic rats from days 0.5 to 10.5 of gestation. Embryos and decidua were explanted on day 10.5 of gestation. MMPs and TIMPs were evaluated by direct, reverse and in situ zymography, and NO production by the evaluation of its stable metabolites: nitrates/nitrites. We found that the malformation rate was increased in the diabetic animals (p<0.001). MMP9 and MMP2 activities were enhanced both in embryos (p<0.05) and decidua (p<0.001) from diabetic rats when compared to controls. Regarding the endogenous MMP inhibitors, TIMP2 and TIMP3 levels were found increased in both embryos (p<0.01) and decidua (p<0.05) from diabetic rats. In situ zymography localized an enhanced MMP/TIMP ratio mainly in the embryonic neural tube, somites and heart, as well as in the surrounding decidua. Maternal treatments with folate did not change MMPs activities but increased TIMP2 and TIMP3 levels (p<0.05) in the embryos from diabetic rats. Nitrates/nitrites concentrations were increased in embryos (p<0.001) and decidua (p<0.01) from diabetic rats and maternal treatments with folate reduced nitrate/nitrite concentrations in diabetic decidua (p<0.05). These changes were observed together with a reduction in both resorption (p<0.001) and malformation rates (p<0.05) in the folate-treated diabetic animals. Conclusion: Maternal diabetes leads to a disbalance in MMPs/TIMPs and NO production in the embryo and the decidua, and the improvement of these parameters are probably mechanisms involved in prevention of diabetes-induced embryo malformations by maternal treatments with folate.