Basic fibroblast growth factor causes urinary bladder overactivity through gap junction generation in the smooth muscle
Basic fibroblast growth factor causes urinary bladder overactivity through gap junction generation in the smooth muscle
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DOI：
10.1152/ajprenal.90207.2008
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发表时间：
2009-07-01
影响因子：
4.2
通讯作者：
Ogawa, Osamu
中科院分区：
文献类型：
--
作者：
Imamura, Masaaki;Negoro, Hiromitsu;Ogawa, Osamu
Imamura M、Negoro H、Kanematsu A、Yamamoto S、Kimura Y、Nagane K、Yamasaki T、Kanatani I、Ito N、Tabata Y、Okawa O。碱性成纤维细胞生长因子通过平滑肌中间隙连接的生成导致膀胱过度活动。 Am J Physiol Renal Physiol 297: F46-F54, 2009。首次发表于 2009 年 4 月 27 日； doi:10.1152/ajprenal.90207.2008.-膀胱过度活动症是一种非常普遍的临床病症，通常由膀胱出口梗阻 (BOO) 引起。膀胱平滑肌细胞 (BSMC) 通过间隙连接增强的耦合已被假设为 BOO 中肌源性膀胱过度活动的机制，尽管人们对这种变化背后的调节系统知之甚少。在此，我们报道碱性成纤维细胞生长因子 (bFGF) 和连接蛋白 43（一种膀胱间隙连接蛋白）与膀胱过度活动有关。大鼠尿道收缩产生的 BOO 导致膀胱尿路上皮和肌肉层中的 bFGF 和连接蛋白 43 水平分别升高，并且来自这些膀胱的肌肉条比来自假手术对照的肌肉条对胆碱能激动剂更敏感。体外 bFGF 处理通过 ERK1/2 途径增加培养的大鼠 BSMC 中连接蛋白 43 的表达。这一发现得到了另一个体内模型的支持，其中固定在大鼠膀胱壁上的明胶水凝胶释放的 bFGF 导致肌肉层中连接蛋白 43 上调和间隙连接形成。该模型中的膀胱肌条显示出对胆碱能激动剂的敏感性增加，而胆碱能激动剂可通过用α-甘草次酸抑制间隙连接功能来阻断。该模型的膀胱测量分析显示逼尿肌过度活动的典型特征，例如排尿频率显着增加和膀胱容量减少。这些发现表明，来自尿路上皮的 bFGF 可以通过平滑肌中间隙连接的产生诱导膀胱对乙酰胆碱过敏，从而导致梗阻膀胱的肌源性过度活动。
Imamura M, Negoro H, Kanematsu A, Yamamoto S, Kimura Y, Nagane K, Yamasaki T, Kanatani I, Ito N, Tabata Y, Ogawa O. Basic fibroblast growth factor causes urinary bladder overactivity through gap junction generation in the smooth muscle. Am J Physiol Renal Physiol 297: F46-F54, 2009. First published April 27, 2009; doi:10.1152/ajprenal.90207.2008.-Overactive bladder is a highly prevalent clinical condition that is often caused by bladder outlet obstruction ( BOO). Increased coupling of bladder smooth muscle cells (BSMC) via gap junctions has been hypothesized as a mechanism for myogenic bladder overactivity in BOO, although little is known about the regulatory system underlying such changes. Here, we report the involvement of basic fibroblast growth factor ( bFGF) and connexin 43, a bladder gap junction protein, in bladder overactivity. BOO created by urethral constriction in rats resulted in elevated bFGF and connexin 43 levels in the bladder urothelium and muscle layer, respectively, and muscle strips from these bladders were more sensitive than those from sham-operated controls to a cholinergic agonist. In vitro bFGF treatment increased connexin 43 expression in cultured rat BSMC via the ERK1/2 pathway. This finding was supported by another in vivo model, where bFGF released from gelatin hydrogels fixed on rat bladder walls caused connexin 43 upregulation and gap junction formation in the muscle layer. Bladder muscle strips in this model showed increased sensitivity to a cholinergic agonist that was blocked by inhibition of gap junction function with alpha-glycyrrhetinic acid. Cystometric analyses of this model showed typical features of detrusor overactivity such as significantly increased micturition frequency and decreased bladder capacity. These findings suggest that bFGF from the urothelium could induce bladder hypersensitivity to acetylcholine via gap junction generation in the smooth muscle, thereby contributing to the myogenic overactivity of obstructed bladders.