Role of Angiotensin II in Bladder Dysfunction

间质性膀胱炎/膀胱疼痛综合征（IC/BPS）与排尿频率增加、排尿困难、膀胱纤维化和慢性盆腔疼痛相关。它影响了美国2.5%至6.7%的女性。目前的治疗方案对所有患者无效，并伴有有害的副作用。IC/BPS中一种未充分研究的信号肽/激素是血管紧张素II（Ang II）。除了其在血管收缩、水潴留和应激反应中的作用外，Ang II还通过促进氧化应激、促炎细胞因子释放和纤维化而导致伤害感受和感觉敏感性增加，从而导致多种疾病。然而，与其他器官系统（心脏、肾脏和肺）相比，在病理生理条件下，对膀胱中Ang II信号传导的功能知之甚少。在IC/BPS病理学和血管紧张素信号传导之间存在几种有趣的联系。1)IC/BPS患者的肥大细胞浸润增加，这是肾素和Ang II增加的来源。2)IC/BPS患者和动物疾病模型的膀胱氧化应激增加，血管紧张素信号增加ROS的产生。 3)IC/BPS患者炎症介质的表达增加，其可通过Ang II下游信号传导释放。4)在IC/BPS的患者和动物模型中观察到纤维化，并且Ang II信号传导与心脏、肺、肝和肾中的纤维化有关。鉴于IC/BPS研究的基础证明了局部肥大细胞/巨噬细胞、氧化应激、炎症介质、纤维化的增加，以及大量描述其他组织中类似Ang II分子信号传导事件的文献，我们认为进一步探索Ang II在膀胱疾病中的作用是必要的。我们假设血管紧张素II信号在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展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（AT 1 R）（Aim 1）和血管紧张素2型受体（AT 2 R）（Aim 2）对氧化应激、促炎分子释放和与IC/BPS样症状小鼠模型相关的纤维化的病理生理学症状的贡献来检验这一假设。我们将使用药理学和转基因方法来确定AT 1 R和AT 2 R在膀胱中的细胞类型表达，表达水平在疾病条件下如何变化，以及它们在发展和维持疾病症状中的重要性。这项提议将有助于确定血管紧张素II在IC/BPS中的作用，可能使这种疾病接受广泛可用且安全的血管紧张素信号传导抑制剂的治疗，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.