Dysregulation of cGMP-dependent protein kinase 1 (PKG-1) impairs erectile function in diabetic rats: Influence of in vivo gene therapy of PKG1α

OBJECTIVES: To investigate the expression of cGMP-dependent protein kinase 1 (PKG1)α and PKG1β in the corpus cavernosum, and to evaluate the effect of adenoviral gene transfer of PKG1α to the erectile compartment on erectile function in a rat model of diabetes. MATERIALS AND METHODS: Diabetic (DM; induced by streptozotocin) male Sprague Dawley rats were transfected with adenoviruses (AdCMVβgal or AdCMVPKG1α, in 10 rats each) 2 months after the induction of DM. Intracavernosal pressure (ICP) during stimulation of the cavernosal nerve (CN) was assessed, and compared with mean arterial pressure (MAP). Erectile tissue was harvested for Western blot analysis, immunohistochemistry and total PKG activity. Ten age-matched rats without DM served as the control. RESULTS: Compared to controls, AdCMVβgal-transfected DM rats had significantly lower peak ICP responses, ICP/MAP ratios, and filling rates during CN stimulation. In DM rats transfected with AdCMVPKG1α, peak ICP, ICP/MAP ratios and filling rates were significantly better than in DM rats transfected with the reporter gene. As assessed by Western blot and immunohistochemistry, expression of PKG1α and PKG1β was lower in corporal tissue from DM AdCMVβgal-transfected rats than in controls. PKG1α expression was improved after AdCMVPKG1α gene therapy. Total PKG activity was lower in DM rat corporal tissue than in controls, and PKG1α gene transfer significantly improved DM corporal PKG activity to a value greater than in the control. CONCLUSION: PKG1α and PKG1β activities are reduced in the erectile tissue of the diabetic rat, and gene transfer of PKG1α to the penis restored PKG activity and erectile function in vivo in diabetic rats. Gene therapy procedures targeting PKG1α might be an interesting future therapeutic approach to overcome diabetic erectile dysfunction resistant to oral pharmacotherapy.