Testosterone regulates RhoA/Rho-kinase signaling in two distinct animal models of chemical diabetes

Linda Vignozzi, Annamaria Morelli, Sandra Filippi, Stefano Ambrosini, Rosa Mancina, Michaela Luconi, Sara Mungai, Gabriella Barbara Vannelli, Xin-Hua Zhang, Gianni Forti, Mario Maggi
Journal of Sexual Medicine 2007, 4 (3): 620-30; discussion 631-32

INTRODUCTION: The contractile RhoA/Rho-kinase (ROCK) signaling pathway is upregulated in penile tissue in animal models of experimental diabetes and has been proposed to contribute to diabetes-related erectile dysfunction (ED).

AIM: To investigate the effect of testosterone (T) on the RhoA/ROCK signaling in diabetes.

METHODS: We used two distinct animal models of chemical diabetes (alloxan-induced in the rabbit and streptozotocin-induced in the rat) with or not T supplementation.

MAIN OUTCOME MEASURES: The effect of diabetes and T supplementation on RhoA/ROCK signaling was evaluated as responsiveness to the selective ROCK inhibitor Y-27632 either by "in vitro" contractility study (diabetic rabbit) or "in vivo" as erectile response elicited by intracavernous injections (diabetic rats). RhoA/ROCK gene and protein expression were also analyzed.

RESULTS: In both models, hypogonadism was observed, characterized by reduced T plasma level and androgen-dependent accessory glands atrophy. Diabetic animals showed a significant increase in responsiveness to increasing concentrations of Y-27632. T substitution (30 mg/kg, weekly) completely prevented hypogonadism and diabetes-induced penile hypersensitivity to Y-27632. To test whether this effect was due to a T-dependent regulation of RhoA/ROCK gene expression, we measured RhoA/ROCK mRNA. Both isoforms of ROCK (ROCK1/ROCK2) were analyzed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) in rat penile samples. We found that ROCK1 mRNA was significantly increased (P < 0.05) in penile tissues from diabetic animals and maintained at the control values by T, as also confirmed by semiquantitative RT-PCR in rabbit. Conversely, RhoA and ROCK2 mRNA expression was not influenced either by diabetic condition or by T administration. Accordingly, ROCK1 protein expression, as evaluated by Western blot and immunohistochemistry analysis, was increased in penile samples from diabetic animals and normalized by T.

CONCLUSIONS: Our data further support the hypothesis that the overexpression of RhoA/ROCK signaling contributes to diabetes-related ED. Moreover, treating hypogonadism in course of diabetes may maintain erectile function also by normalizing RhoA/ROCK pathway upregulation.

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