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

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. To investigate whether the S1PR2 receptor antagonist JTE-013 could improve DM-induced ED (DMED) in rats and to explore the potential mechanisms. We used 50 male Sprague Dawley rats (8weeks 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 4weeks. The rest were fed under the same conditions for 4weeks. 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. 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. JTE-013 supplementation partially improved erectile function in rats with DMED, likely by inhibiting smooth muscle contraction, corporal fibrosis, and apoptosis.