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

描述(由申请人提供)： 6.项目摘要/摘要锂治疗双相情感障碍引起的肾源性尿崩症(NDI)是退伍军人的主要肾脏问题之一。NDI是一种虚弱的疾病，发病率甚至死亡率都会增加，尤其是在老年退伍军人中。目前使用的NDI治疗方法取得了不同程度的成功，也出现了副作用，包括锂中毒。基于对锂诱导的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疗法应该会导致疗效的提高和副作用的减少。我们在当前资助期间开展的研究为嘌呤能信号在锂诱导的NDI发生中的潜在作用提供了重要的见解。它们是：(I)嘌呤能信号可能在平衡精氨酸加压素(AVP)对尿药浓度机制的影响方面发挥潜在的主导作用；(Ii)在锂诱导的NDI中，髓质集合管中的嘌呤能信号被敏化，并涉及多种亚型的P2Y受体；以及(Iii)P2Y2受体基因敲除小鼠显著抵抗锂诱导的NDI的发展，这表明嘌呤能信号在锂诱导的NDI的发生中可能起作用。基于我们新颖而有意义的观察，我们假设，更深入地了解肾脏嘌呤能信号在LI诱导的NDI中的作用可以提供更好的治疗方式。一类针对嘌呤能信号转导的新药可能会提高现有药物在联合治疗中的安全性和/或有效性，或者在LI诱导的NDI的治疗中取代它们。本项目的具体目标是：1)利用P2Y2受体基因敲除小鼠和野生型小鼠，研究嘌呤能信号在Li诱导的AVP抵抗中的作用；2)利用原代培养的小鼠内髓集合管细胞，研究嘌呤能信号在Li诱导的髓质集合管AVP抵抗中的作用；3)在钝化的嘌呤信号背景下，观察阿米洛利和COX-2抑制对Li诱导的NDI的影响。为了实现我们的目标，我们将使用P2Y2受体基因敲除的小鼠、大鼠和细胞培养模型，并使用分子、功能、免疫组织化学和细胞信号转导技术。

DESCRIPTION (provided by applicant): 6. Project Summary/Abstract Nephrogenic diabetes insipidus (NDI) due to lithium therapy for bipolar disorder is one of the major nephrological problems among Veterans. NDI is a debilitating condition with an elevated risk of morbidity and even mortality, especially in elderly Veterans. Currently used therapeutic modalities for NDI are encountered with varying degrees of success as well as side effects, including lithium intoxication. Refinement and/or replacement of the current side effect-prone therapies with new drugs based on an improved understanding of molecular pathophysiology of lithium-induced NDI should result in improved efficacy and fewer side effects. Research carried out by us during the current funding period provided significant insights into the potential role of purinergic signaling in the genesis of lithium-induced NDI. These are: (i) purinergic signaling may play a potential overarching role in balancing the effect of arginine vasopressin (AVP) on the urinary concentration mechanism; (ii) in lithium-induced NDI, purinergic signaling in the medullary collecting duct is sensitized and involves more than one subtype of P2Y receptors; and (iii) P2Y2 receptor gene knockout mice are significantly resistant to the development of lithium-induced NDI, suggesting the potential role of purinergic signaling in the genesis of lithium-induced NDI. Based on our novel and significant observations we hypothesize that a deeper understanding of the role of renal purinergic signaling in Li-induced NDI offers better therapeutic modalities. A new class of drugs that target purinergic signaling may improve the safety and/or efficacy of the current medications in combination therapies, or replace them in the treatment of Li-induced NDI. The specific objective of the project are: 1) to investigate the role of purinergic signaling in the development of Li-induced AVP resistance using P2Y2 receptor knockout and wild type mice; 2) to investigate the role of purinergic signaling in Li-induced AVP resistance of medullary collecting duct using primary cultures of mouse inner medullary collecting duct cells; and 3) to investigate the effect of amiloride and COX-2 inhibition on Li-induced NDI in a background of blunted purinergic signaling. To achieve our objectives we will use P2Y2 receptor knockout mice, rats and cell culture models, and employ molecular, functional, immunohistochemical and cell signaling techniques.