Role of increased penile expression of transforming growth factor-beta1 and activation of the Smad signaling pathway in erectile dysfunction in streptozotocin-induced diabetic rats

Abstract

Introduction: It has been suggested that transforming growth factor-beta1 (TGF-beta1) plays an important role in the pathogenesis of diabetes-induced erectile dysfunction.

Aim: To investigate the expression and activity of Smad transcriptional factors, the key molecules for the initiation of TGF-beta-mediated fibrosis, in the penis of streptozotocin (STZ)-induced diabetic rats.

Methods: Fifty-two 8-week-old Sprague-Dawley rats were used and divided into control and diabetic groups. Diabetes was induced by an intravenous injection of STZ.

Main outcome measures: Eight weeks later, erectile function was measured by electrical stimulation of the cavernous nerve (N = 12 per group). The penis was harvested and stained with Masson trichrome or antibody to TGF-beta1, phospho-Smad2 (P-Smad2), smooth muscle alpha-actin, and factor VIII (N = 12 per group). Penis specimens from a separate group of animals were used for TGF-beta1 enzyme-linked immunosorbent assay (ELISA), P-Smad2/Smad2, phospho-Smad3 (P-Smad3)/Smad3, fibronectin, collagen I, and collagen IV western blot, or hydroxyproline determination.

Results: Erectile function was significantly reduced in diabetic rats compared with that in controls. The expression of TGF-beta1, P-Smad2, and P-Smad3 protein evaluated by ELISA or western blot was higher in diabetic rats than in controls. Compared with that in control rats, P-Smad2 expression was higher mainly in smooth muscle cells and fibroblasts of diabetic rats, whereas no significant differences were noted in endothelial cells or in the dorsal nerve bundle. Cavernous smooth muscle and endothelial cell contents were lower in diabetic rats than in controls. Cavernous fibronectin, collagen IV, and hydroxyproline content was significantly higher in diabetic rats than in controls.

Conclusion: Upregulation of TGF-beta1 and activation of the Smad signaling pathway in the penis of diabetic rats might play important roles in diabetes-induced structural changes and deterioration of erectile function.