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一种，在退伍军人中很常见。目前，约30%的躁郁症退伍军人接受长期锂（Li）治疗，这也有效地预防了自杀倾向。然而，锂的长期使用受到肾源性尿崩症（NDI）发展的限制，这是一种肾脏无法浓缩尿液导致水和电解质过度流失的疾病。目前用于治疗NDI的方式遇到了不同程度的成功以及副作用。基于对Li诱导的NDI的分子病理生理学的更好理解，用新药改进和/或替代目前的副作用倾向性疗法应导致改善的疗效和更少的副作用。在这种情况下，我们发现，信号系统，称为嘌呤信号，可以有针对性地改善锂诱导的NDI。本项目的目标是破译ADP激活的P2 Y12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的病理生理学的认识产生重大影响，并有可能开发新的治疗方法。我们观察到，P2 Y12-R在肾脏中表达，并且其被广泛使用的抗凝药物硫酸氢氯吡格雷（Plaidogrel（r））选择性阻断，增加肾脏保存水的能力，并改善Li诱导的NDI。基于这些新的观察结果，我们假设阻断P2 Y12-R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，P2 Y12-R阻断抑制锂诱导的前列腺素和一氧化氮产生的增加，以及氧化应激，从而有助于整体有益的效果。为了解决这一假设，我们提出了三个具体的目标，并使用大鼠和小鼠模型，培养的肾集合管细胞，和代理商，通过P2 Y12 R调节信号。目的1研究P2 Y12-R对锂诱导的集合管APQ 2表达降低的影响及其可能的机制，目的2研究P2 Y12-R阻断对锂诱导的前列腺素和一氧化氮产生增加和氧化应激的有益作用。目的#3是评估靶向P2 Y12-R（伴随或不伴随P2 Y2-R的钝化）对肾脏中Li诱导的NDI、集合管重塑和细胞增殖的治疗益处。因此，该提议基于新的概念、观察和假设，并且其将Li诱导的NDI的研究和治疗的当前焦点从主要对抗抗AVP作用的那些转移到增强肾脏对AVP的敏感性的那些，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.