Localization of Increased Insulin-Like Growth Factor Binding Protein-3 in Diabetic Rat Penis: Implications for Erectile Dysfunction

Abstract

Diabetes-induced erectile dysfunction (ED) is assumed to result from neurovascular abnormalities. However, the entire picture of the molecular mechanisms underlying ED has not yet been clarified. To elucidate the possible elements involved in ED in diabetes mellitus, we performed broad-scale gene expression profiling using cDNA array in the penis of streptozotocin-induced diabetic rats. Northern blot analysis was performed to examine the course of the mRNA expression encoded by the identified gene. Immunohistochemistry was performed to identify the cellular localization of the encoded protein. Of the genes investigated, the expression level of insulin-like growth factor binding protein 3 (IGFBP-3) was greatly increased at 12 weeks after streptozotocin treatment. The levels of ErbB3 epidermal growth factor receptor-related proto-oncogene, G1/S-specific cyclin D2, hepatic neutral cholesteryl ester hydrolase precursor, UDP-galactose ceramide galactosyltransferase, and serine protease RNK-Met-1 were markedly decreased. Increased levels of IGFBP-3 mRNA were demonstrated as early as 2 weeks after induction of hyperglycemia. Increased IGFBP-3 protein was localized to the epithelium of the urethra, penile endothelium, and smooth muscle in the corpus cavernosum. Significant depletion of the smooth muscle density relative to the connective tissue was first observed in the penis of the 8-week diabetic rats, and a significant reduction in the intracavernous pressure was demonstrated only at 12 weeks after the induction of hyperglycemia. These results suggest that the increased expression of IGFBP-3 during hyperglycemia might play an important role in the development of ED.