BMP/Smad signaling in diabetic small intestine (Artículo completo en revisión)

HONORÉ S. M.; GENTA S. B.; VILLECCO E. I.; SÁNCHEZ S. S.

BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS

Elsevier

Año: 2009

0304-4165

Background: Gastrointestinal disorders are common complications in the diabetic state, however, the mechanisms responsible for this are not fully understood. Here, we have investigated the involvement of the bone morphogenetic proteins (BMPs), in diabetic intestinal dysfunction. Methods: This study used an STZ-induced experimental model in mouse. Specimens from normal and diabetic intestine were assessed by RT-PCR and Western immunoblotting in order to investigate BMP2, BMP4, BMP6, BMP7, BMPRIa, BMPRII, Smad1 and Smad4 at mRNA. Protein expression profile of BMP2, BMP4 and BMP6, BMPRIa and p-Smad1 was also analized by Western immunoblotting. We determined in situ the spatial expression pattern of BMPs and BMPRs using immunohistochemical methods. Specific staining that detects activated Smad proteins was also used. Myenteric plexus neurones and glial cells were assessed using specific markers. In addition, epithelial cell proliferation and myenteric ganglia cell apoptosis was evaluated by means of indirect and direct techniques. Results: We found that experimental diabetes deregulates BMP/Smad signaling molecules on the mucosa and muscle layers of the diabetic jejunum. Diabetes resulted in a prominent proliferative activity in the mucosa accompanied by a decreased BMP4 activity in lamina propia cells. We observed a thicker smooth muscle layer with increased BMP6 expression. A loss of enteric neurons by apoptosis was correlated with an ectopic BMP4, increased BMPRIa and nuclear p-Smad1 expression in the myenteric plexus. Conclusions: Our data demonstrate for the first time a deregulation of the BMPs/Smad signaling pathway in the diabetic intestine. General significance: all findings presented herein suggest that BMPs/Smad are an important feature during intestinal pathophysiology.