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: 9040769
• 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/9040769
• 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; 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; novel therapeutics; phosphoric diester hydrolase; prevent; public health relevance; receptor; success; suicidal; targeted treatment; urinary; vasopressin resistant diabetes insipidus; 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）： 在部署到伊拉克和阿富汗的200万部队中，约有20％可能需要治疗创伤后应激障碍（PTSD）。双相情感障碍，PTSD的续集在退伍军人中很常见。目前，大约30％的双极退伍军人接受慢性锂（LI）治疗，这也有效地阻止了自杀趋势。然而，锂的长期使用受到肾脏基质糖尿病（NDI）的发展的限制，在这种疾病中，儿童无法浓缩尿液，导致水和电解质过量损失。目前使用的NDI治疗方式遇到了不同程度的成功和副作用。基于对LI诱导的NDI的分子病理生理学的了解，将目前副作用疗法的细化和/或替换为新药，应提高效率和更少的副作用。在这种情况下，我们发现一个称为嘌呤能信号传导的信号系统可以针对改善Li诱导的NDI。该项目的目的是破译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LI诱导的NDI病理生理学的了解产生重大影响，并有可能发展新疗法。我们观察到P2Y12-R在肾脏中表达，其选择性封锁是通过氯吡格雷硫酸盐（Plavix（r））（一种更广泛的使用的抗闭合药物）提高了肾脏保护水的能力，并改善了LI诱导的NDI。基于这些新颖的观察结果，我们假设P2Y12-R的阻断通过将肾脏收集导管重新敏感为AVP的作用，从而改善了Li诱导的NDI。我们进一步假设P2Y12-R桶抑制了LI诱导的前列腺样和一氧化氮的增加以及氧化应激，从而有助于整体有益作用。为了解决这一假设，我们提出了三个特定目标，并使用大鼠和小鼠模型，培养的肾脏收集管细胞以及调节P2Y12R信号传导的试剂。 AIM＃1是研究P2Y12-R对收集管中APQ2表达降低以及涉及的潜在机制的影响。 AIM＃2是研究P2Y12-R桶对LI诱导的前类氧化物和一氧化氮产生以及氧化应激的增加的有益作用。 AIM＃3是评估靶向P2Y12-R（有或不同时染色P2Y2-R）在LI诱导的NDI上，收集肾脏中的导管重塑和细胞增殖的治疗益处。这是基于一种新颖的概念，观察结果和假设，并且将目前的LI诱导NDI的研究和疗法的重点转移到了主要的抗AVP效应的主要概念，从而将肾脏对AVP的敏感性提高到AVP的抗AVP的效果的重点，从而使副作用最小。