Targeting Renal Purinergic Signaling for the Treatment of Lithium-induced NDI

靶向肾脏嘌呤信号传导治疗锂诱导的 NDI

• 批准号: 8921910
• 负责人: BELLAMKONDA K KISHORE
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8921910
• 关键词: Address; Adenylate Cyclase; Adverse effects; Afghanistan; Applications Grants; Argipressin; Bipolar Disorder; Blood; Cell Proliferation; Cells; Chronic; Clinical; Coagulation Process; Communities; Coupled; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Development; Dinoprostone; Duct (organ) structure; Electrolytes; Functional disorder; Funding; Genetic; Goals; Healthcare; Iraq; Kidney; Knowledge; Lithium; Membrane; Military Personnel; Mission; Modality; Molecular; Natriuresis; Nephrogenic Diabetes Insipidus; Nitric Oxide; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Physiology; Plavix; Polyuria; Population Heterogeneity; Post-Traumatic Stress Disorders; Prevalence; Process; Production; Prostaglandins; Proteins; Rattus; Research; Resistance; Rest; Rodent; Role; Signal Transduction; Suicide; System; Therapeutic; Therapeutic Studies; Therapeutic Uses; Tissues; Urine; Veterans; Water; aquaporin-2; base; cGMP production; clopidogrel; collecting tubule structure; improved; innovation; mouse model; novel; phosphoric diester hydrolase; prevent; public health relevance; receptor; success; suicidal; targeted treatment; urinary; water channel

 DESCRIPTION (provided by applicant): Approximately 20% of the 2 million troops deployed to Iraq and Afghanistan may require treatment for post-traumatic stress disorder (PTSD). Bipolar disorder, a sequel to PTSD is common among Veterans. Currently about 30% of the bipolar Veterans receive chronic lithium (Li) therapy, which also effectively prevents suicidal tendencies. However, chronic usage of lithium is limited by the development of nephrogenic diabetes insipidus (NDI), a condition in which the kidneys cannot concentrate urine resulting in excessive loss of water and electrolytes. Currently used modalities for the treatment of NDI are encountered with varying degrees of success as well as side effects. Refinement and/or replacement of the current side effect-prone therapies with new drugs based on an improved understanding of molecular pathophysiology of Li-induced NDI should result in improved efficacy and fewer side effects. In this context, we discovered that a signaling system, called purinergic signaling, can be targeted to ameliorate Li-induced NDI. The goal of this project is to decipher the role of ADP-activated P2Y12 receptor (R) in Li- induced NDI. This will have significant impact on our current knowledge of pathophysiology of Li-induced NDI, with a potential for the development of novel therapies. We observed that P2Y12-R is expressed in the kidney, and its selective blockade by clopidogrel bisulfate (Plavix(r)), a widely used anti-clotting drug, increases the ability of the kidney to conserve water, and ameliorates Li-induced NDI. Based on these novel observations, we hypothesize that blockade of P2Y12-R ameliorates Li-induced NDI by re- sensitizing the kidney collecting duct to the action of AVP. We further hypothesize that P2Y12-R blockade suppresses Li-induced increases in prostanoid and nitric oxide production, and oxidative stress, thus contributing to overall beneficial effect. To address this hypothesis, we propose three specific aims, and use rat and mouse models, cultured kidney collecting duct cells, and agents that modulate signaling through for P2Y12R. Aim # 1 is to investigate the effect of P2Y12-R on Li-induced decrease in APQ2 expression in the collecting duct and the potential mechanisms involved in it. Aim # 2 is to investigate the beneficial effects of P2Y12-R blockade on Li-induced increases in prostanoid and nitric oxide production and oxidative stress. Aim # 3 is to evaluate the therapeutic benefits of targeting P2Y12-R (with or without concurrent blunting of P2Y2-R) on Li-induced NDI, collecting duct remodeling and cell proliferation in the kidney. Thus, this proposal is based on a novel concept, observations, and hypothesis, and it shifts the current focus of research and therapies for Li-induced NDI from predominantly the ones that counter anti- AVP effects to the ones that enhance the sensitivity of the kidney to AVP, thereby ensuing minimal side effects.

 描述（由申请人提供）： 部署到伊拉克和阿富汗的 200 万士兵中，大约有 20% 可能需要接受创伤后应激障碍 (PTSD) 治疗。双相情感障碍是创伤后应激障碍的后遗症，在退伍军人中很常见。目前，大约 30% 的双相情感障碍退伍军人接受长期锂 (Li) 治疗，这也能有效防止自杀倾向。然而，长期使用锂会受到肾性尿崩症（NDI）的限制，肾性尿崩症是一种肾脏无法浓缩尿液，导致水分和电解质过度流失的疾病。目前使用的 NDI 治疗方法取得了不同程度的成功，但也存在副作用。基于对锂诱导的 NDI 分子病理生理学的深入了解，用新药改进和/或替换当前容易产生副作用的疗法，应该会提高疗效并减少副作用。在这种情况下，我们发现一种称为嘌呤能信号传导的信号系统可以改善锂诱导的 NDI。该项目的目标是破译 ADP 激活的 P2Y12 受体 (R) 在 Li 诱导的 NDI 中的作用。这将对我们目前对锂诱导的 NDI 病理生理学的了解产生重大影响，并具有开发新疗法的潜力。我们观察到 P2Y12-R 在肾脏中表达，广泛使用的抗凝血药物氯吡格雷硫酸氢盐 (Plavix(r)) 选择性阻断 P2Y12-R，可增加肾脏保存水分的能力，并改善锂诱导的 NDI。基于这些新的观察结果，我们假设 P2Y12-R 的阻断通过使肾集合管对 AVP 的作用重新敏感来改善 Li 诱导的 NDI。我们进一步假设 P2Y12-R 阻断可抑制锂诱导的前列腺素和一氧化氮生成以及氧化应激的增加，从而有助于总体有益效果。为了解决这一假设，我们提出了三个具体目标，并使用大鼠和小鼠模型、培养的肾集合管细胞以及调节 P2Y12R 信号传导的药物。目标#1 是研究 P2Y12-R 对 Li 诱导的集合管中 APQ2 表达减少的影响及其潜在机制。目标 2 是研究 P2Y12-R 阻断对 Li 诱导的前列腺素和一氧化氮生成以及氧化应激增加的有益影响。目标#3是评估靶向P2Y12-R（有或没有同时钝化P2Y2-R）对Li诱导的NDI、集合管重塑和肾脏细胞增殖的治疗益处。因此，该提议基于一个新的概念、观察和假设，它将当前锂诱导的 NDI 的研究和治疗重点从主要对抗抗 AVP 效应转移到增强肾脏对 AVP 的敏感性，从而将副作用降至最低。