Impaired heme oxygenase-1 induction in the gastric antrum induces disruption of the interstitial cells of Cajal network in a rat model of streptozotocin-induced diabetes

Background: Streptozotocin (STZ) is known to induce type I diabetes and the loss of the interstitial cells of Cajal (ICC). However, the regulation of heme oxygenase-1 (HO-1) expression, which is reported to protect ICC, has not yet been elucidated in this model. The aim of this study was to investigate the alterations of HO-1 expression and clarify the mechanism of ICC loss in the stomach using the rat model of STZ-induced diabetes. Methods: Streptozotocin (65 mg kg^-1) was intraperitoneally administered to 8-week-old female Wistar rats. Cobalt protoporphyrin (CoPP), an HO-1 inducer, was administered subcutaneously once a week after the STZ injection. The expressions of HO-1 and the receptor tyrosine kinase c-Kit (a marker for ICC) proteins were investigated by western blot analysis and immunofluorescence staining. Key Results: Expression of c-Kit, particularly in the gastric antrum, was significantly decreased at 8 weeks, not at 1 week, compared to those of the control group. Significantly increased induction of HO-1 expression, especially in the gastric corpus but not in the antrum, was observed in the STZ group at 8 weeks after the STZ injection relative to control. CoPP administration significantly up-regulated HO-1 expression in the STZ diabetic group and significantly restored the previously reduced ICC in the gastric antrum. Conclusions & Inferences: Up-regulation of HO-1 expression in the STZ diabetic model was limited to the gastric corpus and impaired up-regulation of HO-1 expression in the gastric antrum likely induced the disruption of the ICC network.