Alterations in MMP-2 activity and in levels of MMPs regulators in foetuses from diabetic rats

JAWERBAUM A; PUSTOVRH C; CAPOBIANCO E; WHITE V; HIGA R; GONZÁLEZ E

Luso

Congreso; 36th Annual Meeting of the Diabetes in Pregnancy Study Group (DPSG; 2004

Diabetes in Pregnancy Study Group, EASD

Background and aim: diabetes in the mother confers an increased risk for spontaneous abortion, congenital malformations, abnormal foetal growth and predisposes to diseases in the adult life. Matrix metalloproteinases (MMPs) are proteolytic enzymes regulated by NO, involved in remodeling processes taking place during foetal development. 15deoxydelta12,14PGJ2 (15dPGJ2), an endogenous PPARgamma ligand, represses NO production in different tissues. The aim of this work was to evaluate MMP2 activity and its putative regulation by NO and 15dPGJ2 in 14-day fetuses from control and diabetic rats. Methods: diabetes was induced by neonatal administration of streptozotocin (100 mg/kg). MMP2 activity was evaluated by zymography. Nitrates/nitrites (indicating NO production) were measured by Griess method. 15dPGJ2 was measured by EIA. Results: fetuses from diabetic rats showed enhanced MMP2 activity (27% p<0.05) when compared to controls. NO production was enhanced (450% p<0.001) and 15dPGJ2 levels were decreased (71% p<0.001) in fetuses from diabetic rats when related to controls. Sodium nitroprusside (600 mM, a NO donor) stimulated MMP2 activity in fetuses fom control (29% p<0.01) and diabetic (48% p<0.001) animals. NAME (600 mM, a NO inhibitor) reduced foetal MMP2 activity in control and diabetic rats (30%, p<0.01). 15dPGJ2 (2x10-6M) inhibited MMP2 activity in fetuses fom control (30% p<0.05) and diabetic (38% p<0.01) animals. 15dPGJ2 (2 x 10-6M) inhibited NO production in fetuses from control rats (45% p<0.05), but was unable to modify nitrate/nitrite levels in fetuses from diabetic rats. Conclusions: MMP2 activity is enhanced in fetuses from diabetic rats. This may be the result of both increased levels of NO, a positive MMPs regulator, and diminished levels of 15dPGJ2, a negative MMPs regulator. The altered modulation of MMP2 activity is likely to affect foetal development in maternal diabetes.