Hydroxyl Fasudil, an Inhibitor of Rho Signaling, Improves Erectile Function in Diabetic Rats: A Role for Neuronal ROCK

Sena F. Sezen, Gwen Lagoda, Biljana Musicki, Arthur L. Burnett

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Introduction: The pathogenesis of diabetic erectile dysfunction (ED) includes neuropathy, but the molecular basis for neurogenic ED is incompletely understood. The RhoA/ROCK pathway has been implicated in diabetic neuropathy and in ED, but its role in diabetic neurogenic ED is not known. Aims: The aim of this study was to determine whether hydroxyl fasudil, a ROCK inhibitor, affects diabetic neuropathy-related ED. Methods: Type 1 diabetes mellitus was induced in male rats by streptozotocin (75mg/kg, intraperitoneally). After 8 weeks, diabetic rats were administered hydroxyl fasudil, a selective ROCK inhibitor (10mg/kg/day, intraperitoneally) or vehicle, for 4 weeks. Age-matched control, nondiabetic, rats were treated intraperitoneally for 4 weeks with saline. At week 12, after a 2 day washout, neuro-stimulated erectile function was evaluated. Major pelvic ganglia (MPG) were collected for Western blot analysis of RhoA, ROCK-1, ROCK-2, phospho (P)-AKT (Ser473), and P-phosphatase and tensin homolog (P-PTEN) (Ser380/Thr382/383). Main Outcome Measures: Effect of ROCK inhibitor hydroxyl fasudil on erectile function and ROCK/P-AKT/P-PTEN pathway in the MPG of diabetic rats. Results: Erectile response was significantly (P<0.05) reduced in diabetic rats compared with nondiabetic rats and was preserved (P<0.05) in diabetic rats treated with hydroxyl fasudil. In diabetic rats, RhoA and ROCK-2 protein expressions in MPG were increased (P<0.05) and remained increased in hydroxyl fasudil-treated rats. P-AKT (Ser473) expression was decreased (P<0.05), whereas P-PTEN (Ser380/Thr382/383) expression was increased (P<0.05) in MPG of diabetic rats compared with nondiabetic rats, and both were reversed (P<0.05) in diabetic rats treated with hydroxyl fasudil. Conclusion: Improved erectile function and restored P-AKT and P-PTEN in the MPG with hydroxyl fasudil treatment suggest the role of Rho signaling via PTEN/AKT pathway in neurogenic diabetic ED.

Original languageEnglish (US)
Pages (from-to)2164-2171
Number of pages8
JournalJournal of Sexual Medicine
Volume11
Issue number9
DOIs
StatePublished - Sep 2014

Keywords

  • Apoptosis
  • Diabetic Neuropathy
  • Major Pelvic Ganglia
  • P-AKT
  • P-PTEN

ASJC Scopus subject areas

  • General Medicine

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