Chronic hyperglycaemia increases TGFbeta2 signaling and the expression of extracellular matrix proteins in the rat parotid gland.

The majority of the oral manifestations of diabetes mellitus are secondary to a reduced salivary flow, whose causes are still poorly understood. In the kidney, diabetes complications involve increased Transforming Growth Factor beta (TGFbeta) production and the thickening of basement membrane in small vessels. By using immunohistochemistry and western blotting, we studied the expression and signaling of TGFbeta and the distribution of extracellular matrix (ECM) proteins: laminin, fibronectin, collagens III, IV and V in the parotid gland of control and diabetic rats, 30 and 60 days after streptozotocin injection (D30 and D60). At D30, there was an important increase of laminin whereas fibronectin and collagen V were moderately augmented. At D60, an additional increase of all ECM proteins was observed. TGFbeta1 expression was not affected at any time. In contrast, TGFbeta2 levels were significantly higher at D30, concomitant with increased TGFbeta receptor II (TbetaRII), phosphorylated Smads 2 and 3 (pSmads 2-3) and Latent TGFbeta Binding Protein 1 (LTBP1). At D60, TGFbeta2 and TbetaRII were still increased, whereas phosphorylation of Smads was markedly decreased, and LTBP1 returned to control levels. In the control groups, TGFbeta2 labeling was localized preferentially in ductal cells, whereas at D30 and D60 the staining was also observed in acinar cells. The same pattern of distribution was observed for pSmads 2-3 at D30, especially in nuclei. At D60, labeling was weak and dispersed throughout the cytoplasm. These data suggest that hyperglycaemia increases the deposition of ECM proteins in the rat parotid gland, possibly through augmentation of TGFbeta2 expression and signaling.