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

 描述(由申请人提供)： 在部署到伊拉克和阿富汗的200万军队中，大约20%的人可能需要治疗创伤后应激障碍(PTSD)。双相情感障碍是创伤后应激障碍的续集，在退伍军人中很常见。目前，约有30%的双相退伍军人接受慢性锂(Li)治疗，这也有效地防止了自杀倾向。然而，慢性锂的使用受到肾源性尿崩症(NDI)的发展的限制，NDI是一种肾脏不能集中尿液导致水分和电解质过度流失的情况。目前使用的治疗NDI的方法取得了不同程度的成功，也出现了副作用。基于对LI诱导的NDI分子病理生理学的更好的理解，改进和/或用新药取代目前容易产生副作用的治疗方法应该会导致疗效的提高和副作用的减少。在此背景下，我们发现一种称为嘌呤能信号的信号系统可以靶向改善Li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Li诱导的NDI的病理生理学知识产生重大影响，并有可能开发新的治疗方法。我们观察到，P2Y12-R在肾脏中表达，其选择性阻断被广泛使用的抗凝药物Plavix(R)所阻断，增加了肾脏的保水能力，并改善了Li诱导的NDI。基于这些新的观察结果，我们假设，阻断P2Y12-R可以通过使肾脏集合管对AVP的作用重新敏感来改善LI诱导的NDI。我们进一步假设，阻断P2Y12-R可以抑制Li诱导的前列腺素和一氧化氮产生的增加，以及氧化应激，从而有助于整体的有益效果。为了解决这一假设，我们提出了三个具体的目标，并使用了大鼠和小鼠模型、培养的肾脏集合管细胞和调节P2Y12R信号传递的药物。目的研究P2Y12-R对LI诱导的集合管APQ2表达降低的影响及其可能的机制。目的#2研究阻断P2Y12-R对锂诱导的前列腺素和一氧化氮生成增加以及氧化应激的有益影响。目的#3评价靶向P2Y12-R(同时或不同时钝化P2Y2-R)对Li诱导的NDI、集合管重塑和肾脏细胞增殖的治疗作用。因此，这一建议是基于一个新的概念、观察和假设，它将目前LI诱导的NDI的研究和治疗重点从主要对抗AVP效应的研究和治疗转向增强肾脏对AVP的敏感性，从而确保最小的副作用。

 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.