Role of Angiotensin II in Bladder Dysfunction

间质性膀胱炎/膀胱痛综合征(IC/BPS)与排尿频率增加、夜尿、膀胱纤维化和慢性盆腔疼痛相关。在美国，它影响了2.5%到6.7%的女性。目前的治疗方案对所有患者都无效，并与有害的副作用有关。血管紧张素II(Ang II)是IC/BPS中一个研究较少的信号肽/激素。除了在血管收缩、水分保持和应激反应中发挥作用外，Ang II还通过促进氧化应激、促炎细胞因子释放和纤维化而促进几种疾病，从而增加伤害性和感官敏感性。然而，与其他器官系统(心脏、肾脏和肺)相比，对Ang II信号在膀胱中的作用在病理生理条件下的作用知之甚少。IC/BPS病理和血管紧张素信号之间有几个有趣的联系。1)IC/BPS患者肥大细胞浸润增加，这是肾素和Ang II增加的来源。2)IC/BPS患者和动物疾病模型增加了膀胱氧化应激，血管紧张素信号转导增加了ROS的产生。 3)IC/BPS患者体内炎症介质表达增加，其释放可通过Ang II下游信号传导途径实现。4)肝纤维化在IC/BPS的患者和动物模型中观察到，Ang II信号与心、肺、肝和肾的纤维化有关。鉴于IC/BPS研究表明局部肥大细胞/巨噬细胞、氧化应激、炎症介质、纤维化的增加，以及大量文献描述了其他组织中类似的Ang II分子信号事件，我们认为进一步探讨Ang II在膀胱疾病中的作用是必要的。我们假设Ang II信号在与膀胱功能障碍动物模型相关的炎症、氧化损伤和纤维化的发生中起着至关重要的作用。我们将通过解剖血管紧张素1型受体(AT1R)(AIM 1)和血管紧张素2型受体(AT2R)(AIM 2)在氧化应激、促炎分子的释放和与IC/BPS样症状相关的小鼠模型的纤维化的病理生理症状中的作用来检验这一假说。我们将使用药理学和转基因方法来确定AT1R和AT2R在膀胱中的细胞类型表达，在疾病条件下表达水平如何变化，以及它们在疾病症状发展和维持中的重要性。这项建议将有助于确定Ang II在IC/BPS中的作用，有可能使这种疾病获得广泛可用的安全血管紧张素信号抑制剂的治疗，这将对患者的治疗选择和生活质量产生重大影响。

Interstitial cystitis/bladder pain syndrome (IC/BPS) is associated with increased voiding frequency, nocturia, bladder fibrosis, and chronic pelvic pain. It affects between 2.5 to 6.7% of women in the United States. Current treatment options are ineffective for all patients and are associated with detrimental side effects. One understudied signaling peptide/hormone in IC/BPS is angiotensin II (Ang II). In addition to its role in vasoconstriction, water retention, and stress response, Ang II contributes to several diseases by promoting oxidative stress, proinflammatory cytokine release, and fibrosis, resulting in increased nociception and sensory sensitivity. However, compared to other organ systems (cardiac, kidneys, and lungs), relatively little is known about the function of Ang II signaling in the bladder under pathophysiologic conditions. There are several intriguing links between IC/BPS pathology and angiotensin signaling. 1) IC/BPS patients have increased infiltration of mast cells, which represent a source of increased renin and Ang II. 2) IC/BPS patients and animal disease models have increased bladder oxidative stress, and angiotensin signaling increases ROS production. 3) IC/BPS patients have increased expression of inflammatory mediators, which can be released by Ang II downstream signaling. 4) Fibrosis is observed in patients and animal models of IC/BPS, and Ang II signaling has been linked to fibrosis in heart, lungs, liver, and kidneys. Given the foundation of IC/BPS research demonstrating increases in local mast cells/macrophages, oxidative stress, inflammatory mediators, fibrosis, and the wealth of literature describing similar Ang II molecular signaling events in other tissues, we believe it is essential to further explore the role of Ang II in bladder diseases. We hypothesize that Ang II signaling plays a vital role in developing inflammation, oxidative damage, and fibrosis associated with an animal model of bladder dysfunction. We will test this hypothesis by dissecting the contribution of angiotensin type 1 receptor (AT1R) (Aim 1) and angiotensin type 2 receptor (AT2R) (Aim 2) to the pathophysiologic symptoms of oxidative stress, the release of proinflammatory molecules, and fibrosis associated with a mouse model of IC/BPS-like symptoms. We will use pharmacological and transgenic approaches to determine the cell type expression of AT1R and AT2R in the bladder, how expression levels may change under disease conditions and their importance in developing and maintaining disease symptoms. This proposal will help determine the role of Ang II in IC/BPS, potentially opening this disease to treatment with the widely available and safe angiotensin signaling inhibitors, which would have a substantial impact on patient treatment options and quality of life.