JTE-013 supplementation improves erectile dysfunction in rats with streptozotocin-induced type â
diabetes through the inhibition of the rho-kinase pathway, fibrosis, and apoptosis.
Andrology
; 8(2): 497-508, 2020 03.
Article
em En
| MEDLINE
| ID: mdl-31610097
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 ANDMETHODS:
We used 50 male Sprague Dawley rats (8 weeks old) for this experiment. Type â 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-ß1/LIMK2/Cofilin pathway compared with the control group. JTE-013 supplementation significantly ameliorated these pathological changes. DISCUSSION ANDCONCLUSION:
JTE-013 supplementation partially improved erectile function in rats with DMED, likely by inhibiting smooth muscle contraction, corporal fibrosis, and apoptosis.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Pirazóis
/
Piridinas
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Transdução de Sinais
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Diabetes Mellitus Experimental
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Diabetes Mellitus Tipo 1
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Quinases Associadas a rho
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Disfunção Erétil
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article