Department of Clinical Physiopathology, University of Florence, Florence, Italy.
J Steroid Biochem Mol Biol. 2012 Oct;132(1-2):80-92. doi: 10.1016/j.jsbmb.2012.02.007. Epub 2012 Mar 8.
In the male, metabolic syndrome (MetS) is associated to an increased risk of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). A recently established rabbit model of high fat diet (HFD)-induced MetS showed hypogonadism and the presence of prostate gland alterations, including inflammation, hypoxia and fibrosis. The present study investigated whether HFD-induced MetS might also alter bladder structure and function. Testosterone and the farnesoid X receptor (FXR) agonist INT-747, were evaluated for possible effects on HFD bladder. MetS rabbits develop bladder alterations, including fibrosis (reduced muscle/fiber ratio), hypoxia [2-fold increase as compared to regular diet (RD) group], low-grade inflammation (increased leukocyte infiltration and inflammatory markers) and RhoA/ROCK hyperactivity. Bladder strips from HFD rabbits, pre-contracted with carbachol, showed an overactive response to the selective ROCK inhibitor Y-27632. All these HFD-induced bladder alterations were partially blunted by testosterone and almost completely reverted by INT-747. Both treatments prevented some MetS features (glucose intolerance and visceral fat increase), thus suggesting that their effects on bladder could be ascribed to an improvement of the metabolic and/or hypogonadal state. However, a pathogenetic role for hypogonadism has been ruled out as GnRH analog-induced hypogonadal rabbits, fed a regular diet, did not show any detectable bladder alterations. In addition, INT-747 did not revert the MetS-induced hypogonadal state. FXR mRNA was highly expressed in rabbit bladder and positively associated with visceral fat increase. A direct effect of INT-747 on bladder smooth muscle was further suggested by inhibition of RhoA/ROCK-mediated activity by in vitro experiments on isolated cells. In conclusion, HFD-related MetS features are associated to bladder derangements, which are ameliorated by testosterone or INT-747 administration. INT-747 showed the most marked effects in counteracting MetS-related RhoA/ROCK overactivity, thus opening novel therapeutic opportunities for this drug.
在男性中，代谢综合征（MetS）与良性前列腺增生（BPH）和下尿路症状（LUTS）的风险增加有关。最近建立的高脂肪饮食（HFD）诱导的 MetS 兔模型显示出性腺功能减退和前列腺改变，包括炎症、缺氧和纤维化。本研究旨在探讨 HFD 诱导的 MetS 是否也会改变膀胱结构和功能。睾酮和法尼醇 X 受体（FXR）激动剂 INT-747 被评估用于可能对 HFD 膀胱的影响。MetS 兔出现膀胱改变，包括纤维化（肌肉/纤维比例降低）、缺氧（与正常饮食组相比增加 2 倍）、低度炎症（白细胞浸润和炎症标志物增加）和 RhoA/ROCK 活性增加。用 carbachol 预收缩的 HFD 兔膀胱条显示对选择性 ROCK 抑制剂 Y-27632 的过度反应。HFD 诱导的所有这些膀胱改变均被睾酮和 INT-747 部分减弱。两种治疗方法均部分预防了 MetS 特征（葡萄糖耐量受损和内脏脂肪增加），因此，其对膀胱的作用可能归因于代谢和/或性腺功能减退状态的改善。然而，促性腺激素释放激素类似物诱导的性腺功能减退兔，给予正常饮食，并未显示任何可检测到的膀胱改变，因此排除了性腺功能减退的致病作用。此外，INT-747 并未逆转 MetS 诱导的性腺功能减退状态。FXR mRNA 在兔膀胱中高度表达，并与内脏脂肪增加呈正相关。通过在分离细胞上进行的体外实验，进一步提示 INT-747 对膀胱平滑肌的直接作用。总之，HFD 相关的 MetS 特征与膀胱紊乱有关，睾酮或 INT-747 给药可改善这些紊乱。INT-747 在对抗 MetS 相关的 RhoA/ROCK 过度活跃方面表现出最显著的效果，从而为该药物开辟了新的治疗机会。
