Urothelial ATP Signaling and Diabetic Bladder Dysfunction

三磷酸腺苷在膀胱的感觉和运动功能中起着重要作用。ATP 从副交感神经纤维释放的可以兴奋逼尿肌，而从 对膀胱扩张作出反应的尿路上皮可通过激活 传入纤维刺激肾上皮下肌成纤维细胞并诱导其他信号分子的释放 从尿路上皮来的。病理条件可增加神经源性的嘌呤能成分 逼尿肌收缩，也增加尿路上皮ATP的释放。糖尿病患者的各种尿流动力学 可能会出现异常，包括膀胱活动增加。我们已经提议增加 糖尿病膀胱对嘌呤能刺激的敏感性与特异性嘌呤能上调有关 逼尿肌中的受体(P2R)亚型，而ATP信号的放大将直接 促进糖尿病患者膀胱过度活动的发生。根据我们现在掌握的最新发现 有证据表明，在糖尿病的膀胱尿路上皮细胞中，ATP信号也被放大。P2Rs的表达， STZ糖尿病大鼠尿路上皮细胞中的P2X7R和P2X3R亚型显著增加 在STZ-糖尿病的尿路上皮细胞中，膀胱和对ATP的反应更高。这些发现结合了 证明P2X7R激活可以诱导ATP和前列腺素(PGE2)的释放， 提示尿路上皮细胞不仅对三磷酸腺苷敏感，而且对三磷酸腺苷和前列腺素E_2的释放也很敏感。 糖尿病患者膀胱癌的发病率增加。在这种情况下，来自膀胱的传入信号以及 尿路上皮细胞、尿路上皮下肌成纤维细胞和平滑肌细胞之间的联系 显著增强，并可能有助于增加糖尿病患者的膀胱活动。要测试 糖尿病增加尿路上皮细胞三磷酸腺苷信号和膀胱间通讯的假说 膀胱内和来自膀胱的增强的ATP信号有助于 糖尿病患者膀胱功能障碍的发展我们将结合分子生物学， 生物化学、药理学、体外亚细胞成像和整体动物生理学方法。 这些研究有望对特定膜之间的相互作用产生新的理解 参与尿路上皮和膀胱平滑肌细胞间信号转导的受体和通道蛋白 肌肉，并揭示新的治疗靶点和策略，以改善膀胱症状 糖尿病中的功能障碍。

ATP plays important roles in the sensory and motor functions of the urinary bladder. ATP released from parasympathetic fibers can excite the detrusor muscle, and ATP released from the urothelium in response to bladder distension can indirectly modulate detrusor contractility by activating afferent fibers, stimulating suburothelial myofibroblasts and inducing release of other signaling molecules from the urothelium. Pathological conditions can increase the purinergic component of the neurogenic detrusor contraction and also augment urothelial ATP release. In diabetes various urodynamic abnormalities can develop, including increased bladder activity. We have proposed that increased sensitivity of diabetic bladders to purinergic stimulation was related to upregulation of specific purinergic receptor (P2R) subtypes in the detrusor muscle, and that amplification of ATP signaling would directly contribute to the development of bladder overactivity in diabetes. Based on recent findings we have now evidence that ATP signaling in also amplified in the diabetic bladder urothelium. Expression of P2Rs, particularly the P2X7R and P2X3R subtypes, is markedly increased in the urothelium of STZ-diabetic rat bladders and responses to ATP are higher in STZ-diabetic urothelial cells. These findings combined with demonstrations that P2X7R activation can induce release of both ATP and prostaglandin (PGE2), suggest that not only the sensitivity to ATP but also ATP and PGE2 release from urothelial cells is increased in diabetic bladders. In this context, afferent signaling from the bladder as well as ability of urothelial cells, suburothelial myofibroblast and smooth muscle cells to communicate would be significantly enhanced and likely contribute to increase bladder activity in diabetes. To test the hypotheses that diabetes increases urothelial ATP signaling and communication between bladder compartments, and that enhanced ATP signaling within and from the bladder contributes to the development of bladder dysfunction in diabetes we will use a combination of molecular biology, biochemistry, pharmacology, in vitro subcellular imaging and whole animal physiology approaches. These studies are expected to lead to novel understanding of the interplay among specific membrane receptors and channel proteins involved in intercellular signaling between urothelium and bladder smooth muscle, and reveal novel therapeutic targets and strategies to ameliorate the symptoms of bladder dysfunction in diabetes.