Role of Angiotensin II in Bladder Dysfunction

血管紧张素 II 在膀胱功能障碍中的作用

• 批准号: 10555926
• 负责人: Aaron David Mickle
• 金额: $ 29.6万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555926
• 关键词: Affect; Afferent Neurons; American; Angiotensin II; Angiotensins; Animal Disease Models; Animal Model; Behavior; Bladder; Bladder Diseases; Bladder Dysfunction; Cardiac; Disease; Disease model; Event; FDA approved; Fibrosis; Foundations; Frequencies; Functional disorder; Heart; Human; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Interstitial Cystitis; Kidney; Link; Literature; Liver; Lung; Measures; Modeling; Molecular; Myofibroblast; Nociception; Nocturia; Oxidative Stress; Pathology; Patients; Peptide Signal Sequences; Peptides; Peripheral; Pharmacology; Play; Production; Quality of life; Rattus; Receptor Activation; Receptor Signaling; Receptor, Angiotensin, Type 1; Renin; Research; Research Project Grants; Role; Sensory; Shapes; Signal Pathway; Signal Transduction; Source; Symptoms; Testing; Tissue Model; Tissues; Transgenic Organisms; Type 2 Angiotensin II Receptor; United States; Water; Woman; biological adaptation to stress; body system; cell type; chronic painful condition; chronic pelvic pain; cytokine; improved; inhibitor; macrophage; mast cell; mouse model; oxidative damage; peptide hormone; receptor expression; reduce symptoms; side effect; vasoconstriction

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.

间质性膀胱炎/膀胱疼痛综合征 (IC/BPS) 与排尿频率增加、夜尿、膀胱纤维化和慢性盆腔疼痛有关。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都无效，并且会产生有害的副作用。 IC/BPS 中一种正在研究的信号肽/激素是血管紧张素 II (Ang II)。除了在血管收缩、保水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，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，人们对病理生理条件下膀胱中 Ang II 信号传导的功能知之甚少。 IC/BPS 病理学和血管紧张素信号传导之间存在一些有趣的联系。 1) IC/BPS 患者肥大细胞浸润增加，肥大细胞是肾素和血管紧张素 II 增加的来源。 2) IC/BPS患者和动物疾病模型膀胱氧化应激增加，血管紧张素信号传导增加ROS产生。 3）IC/BPS患者炎症介质表达增加，这些炎症介质可以通过Ang II下游信号传导释放。 4) 在 IC/BPS 患者和动物模型中观察到纤维化，Ang II 信号传导与心脏、肺、肝脏和肾脏的纤维化有关。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、纤维化增加，以及描述其他组织中类似 Ang II 分子信号传导事件的大量文献，我们认为有必要进一步探索Ang II 在膀胱疾病中的作用。我们假设 Ang II 信号传导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展中发挥着至关重要的作用。我们将通过剖析血管紧张素 1 型受体 (AT1R)（目标 1）和血管紧张素 2 型受体（AT2R）（目标 2）对氧化应激、促炎分子释放和相关纤维化的病理生理症状的贡献来检验这一假设。具有 IC/BPS 样症状的小鼠模型。我们将使用药理学和转基因方法来确定膀胱中 AT1R 和 AT2R 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。该提案将有助于确定 Ang II 在 IC/BPS 中的作用，有可能使这种疾病可以使用广泛可用且安全的血管紧张素信号抑制剂进行治疗，这将对患者的治疗选择和生活质量产生重大影响。