羟乙基法舒地尔，一种 Rho 信号通路抑制剂，改善糖尿病大鼠的勃起功能：神经元 ROCK 的作用。
Hydroxyl fasudil, an inhibitor of Rho signaling, improves erectile function in diabetic rats: a role for neuronal ROCK.
机构信息
The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
出版信息
J Sex Med. 2014 Sep;11(9):2164-71. doi: 10.1111/jsm.12613. Epub 2014 Jun 12.
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 (75 mg/kg, intraperitoneally). After 8 weeks, diabetic rats were administered hydroxyl fasudil, a selective ROCK inhibitor (10 mg/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 (Ser(473) ), and P-phosphatase and tensin homolog (P-PTEN) (Ser(380) /Thr(382/383) ).
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 (Ser(473) ) expression was decreased (P < 0.05), whereas P-PTEN (Ser(380) /Thr(382/383) ) 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.
简介
糖尿病性勃起功能障碍（ED）的发病机制包括神经病变，但神经源性 ED 的分子基础尚不完全清楚。RhoA/ROCK 通路已被牵涉到糖尿病性神经病变和 ED 中，但它在糖尿病性神经源性 ED 中的作用尚不清楚。
目的
本研究旨在确定 ROCK 抑制剂羟氢哇巴因是否会影响与糖尿病性神经病变相关的 ED。
方法
雄性大鼠通过链脲佐菌素（STZ；75mg/kg，腹腔内注射）诱导 1 型糖尿病。8 周后，糖尿病大鼠给予羟氢哇巴因（一种选择性 ROCK 抑制剂；10mg/kg/天，腹腔内注射）或载体，治疗 4 周。年龄匹配的对照、非糖尿病大鼠用生理盐水腹腔内治疗 4 周。在第 12 周，经过 2 天的洗脱期后，评估神经刺激性勃起功能。收集主要骨盆神经节（MPG）进行 Western blot 分析，以检测 RhoA、ROCK-1、ROCK-2、磷酸化（P）-AKT（Ser(473)）和磷酸酶和张力蛋白同源物（P-PTEN）（Ser(380)/Thr(382/383)）。
主要观察指标
ROCK 抑制剂羟氢哇巴因对糖尿病大鼠 MPG 中勃起功能和 ROCK/P-AKT/P-PTEN 通路的影响。
结果
与非糖尿病大鼠相比，糖尿病大鼠的勃起反应明显降低（P<0.05），而给予羟氢哇巴因治疗的糖尿病大鼠的勃起反应得到保留（P<0.05）。在糖尿病大鼠中，MPG 中的 RhoA 和 ROCK-2 蛋白表达增加（P<0.05），而在羟氢哇巴因治疗的大鼠中仍保持增加。与非糖尿病大鼠相比，糖尿病大鼠 MPG 中的 P-AKT（Ser(473)）表达减少（P<0.05），而 P-PTEN（Ser(380)/Thr(382/383)）表达增加（P<0.05），这两种情况在羟氢哇巴因治疗的糖尿病大鼠中均得到逆转（P<0.05）。
结论
羟氢哇巴因治疗可改善勃起功能，并恢复 MPG 中的 P-AKT 和 P-PTEN，提示 Rho 信号通过 PTEN/AKT 通路在神经源性糖尿病性 ED 中的作用。
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