JTE-013 supplementation improves erectile dysfunction in rats with streptozotocin-induced type Ⅰ diabetes through the inhibition of the rho-kinase pathway, fibrosis, and apoptosis

Abstract

Background: Erectile dysfunction (ED) is a common complication in patients with diabetes mellitus (DM) that severely affects the patients' quality of life. However, the effectiveness of oral phosphodiesterase type 5 inhibitors in these patients is poor. Sphingosine-1-phosphate (S1P) and S1P receptor 2 (S1PR2) are important factors regulating the Rho-kinase pathway, and understanding these factors may provide ideas for new therapeutic strategies for ED.

Objectives: To investigate whether the S1PR2 receptor antagonist JTE-013 could improve DM-induced ED (DMED) in rats and to explore the potential mechanisms.

Materials and methods: We used 50 male Sprague Dawley rats (8 weeks old) for this experiment. Type Ⅰ DM was induced in forty-two rats via streptozotocin administration; the rest of the rats served as controls. Eight weeks after DM induction, rats with ED were selected via an apomorphine test. Eight of them were injected intraperitoneally with JTE-013 each day for 4 weeks. The rest were fed under the same conditions for 4 weeks. Erectile function was measured by cavernous nerve electrostimulation. The expression levels of related signaling pathways were evaluated using Western blotting, real-time PCR, and immunohistochemistry.

Results: Erectile function was significantly impaired in the DMED group compared with the control group and was partially improved in the DMED + JTE-013 group. The expression of S1PR2 and the activity of the RhoA/ROCK/phospho-myosin phosphatase target subunit 1 (p-MYPT1) pathway proteins were higher in the DMED group than in the other two groups, and JTE-013 treatment significantly reduced the expression/activity of these proteins. Furthermore, the DMED group showed severe corporal fibrosis, a higher apoptotic index and increased activity in the TGF-β1/LIMK2/Cofilin pathway compared with the control group. JTE-013 supplementation significantly ameliorated these pathological changes.

Discussion and conclusion: JTE-013 supplementation partially improved erectile function in rats with DMED, likely by inhibiting smooth muscle contraction, corporal fibrosis, and apoptosis.

Keywords: JTE-013; apoptosis; diabetes mellitus; erectile function; fibrosis; rho-kinase.