Reactive oxygen species overproduction and MAP kinase phosphatase-1 degradation are associated with gastroparesis in a streptozotocin-induced male diabetic rat model.

Abstract

Diabetic gastroparesis in human and animal models suggest different developmental causes in females vs males. Previously, we demonstrated that although male and female diabetic gastroparetic rats exhibited similarity in disease pathology, molecular mechanisms were different: slow gastric emptying in male diabetic gastroparetic rats was not associated with the level of expression and dimerization of neuronal nitric oxide synthase α in gastric tissues, as was demonstrated in females. Male gastroparesis may involve other mechanisms, such as oxidative stress. We hypothesize that sustained increased reactive oxygen species (ROS) and degradation of MAP kinase phosphatase-1 with subsequent unregulated activation of c-Jun N-terminal kinase and p38MAP kinase pathways are associated with gastroparesis in a male diabetic rat model. Using a male rat model of diabetic gastroparesis, we analyzed serum and pyloric tissue for ROS and antioxidant enzyme levels using ELISA; MAP kinase phosphatase-1, c-Jun N-terminal kinases, and p38MAP kinase levels utilized western blotting techniques and phospho-specific antibodies. Both diabetic and diabetic gastroparetic rats demonstrated overproduction of ROS. However, loss of MAP kinase phosphatase-1, a MAP kinase pathway negative regulator, with subsequent activation of c-Jun N-terminal kinase 2 and p38MAP kinase pathways, were observed only in diabetic gastroparetic rats. Diabetic rats without gastroparesis had no significant pathway activation. These results suggest that sustained, increased ROS and degradation of MAP kinase phosphatase-1, with subsequent unregulated activation of c-Jun N-terminal kinase and p38MAP kinase pathways, are likely to be factors in diabetic gastroparesis phenotype in a male diabetic rat model.