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: 9907855
• 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 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907855
• 关键词: Address; Adenylate Cyclase; Afghanistan; Applications Grants; Argipressin; Bipolar Disorder; Blood; Cell Proliferation; Chronic; Clinical; Coagulation Process; Communities; Coupled; Cyclic AMP; Development; Dinoprostone; Duct (organ) structure; Ductal Epithelial Cell; Electrolytes; Exposure to; Functional disorder; Funding; Genetic; Goals; Healthcare; Iraq; Kidney; Knowledge; Lithium; Membrane; Military Personnel; Mission; Modality; Molecular; Natriuresis; Nitric Oxide; Oxidative Stress; P2Y2 receptor; PRKCA gene; 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 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; side effect; 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.



项目成果

Prasugrel suppresses development of lithium-induced nephrogenic diabetes insipidus in mice.

普拉格雷可抑制小鼠锂诱导的肾性尿崩症的发展。

• DOI: 10.1007/s11302-017-9555-6
• 发表时间: 2017
• 期刊: Purinergic signalling
• 影响因子: 3.5
• 作者: Zhang,Yue;Peti-Peterdi,János;Brandes,AnnaU;Riquier-Brison,Anne;Carlson,NoelG;Müller,ChristaE;Ecelbarger,CarolynM;Kishore,BellamkondaK
• 通讯作者: Kishore,BellamkondaK

P2Y12 Receptor Localizes in the Renal Collecting Duct and Its Blockade Augments Arginine Vasopressin Action and Alleviates Nephrogenic Diabetes Insipidus.

• DOI: 10.1681/asn.2014010118
• 发表时间: 2015-04
• 期刊: Journal of the American Society of Nephrology : JASN
• 作者: Yue Zhang;J. Peti-Peterdi;C. Müller;N. Carlson;Younis Baqi;D. Strasburg;K. Heiney;Karie G. Villanueva;D. Kohan;B. Kishore

Clopidogrel attenuates lithium-induced alterations in renal water and sodium channels/transporters in mice.

氯吡格雷可减弱锂诱导的小鼠肾水和钠通道/转运蛋白的改变。

• DOI: 10.1007/s11302-015-9469-0
• 发表时间: 2015
• 期刊: Purinergic signalling
• 影响因子: 3.5
• 作者: Zhang,Yue;Peti-Peterdi,János;Heiney,KristinaM;Riquier-Brison,Anne;Carlson,NoelG;Müller,ChristaE;Ecelbarger,CarolynM;Kishore,BellamkondaK
• 通讯作者: Kishore,BellamkondaK

Genetic deletion of ADP-activated P2Y12 receptor ameliorates lithium-induced nephrogenic diabetes insipidus in mice.

ADP 激活的 P2Y12 受体的基因缺失可改善锂诱导的小鼠肾性尿崩症。

• DOI: 10.1111/apha.13191
• 发表时间: 2019
• 期刊: Acta physiologica (Oxford, England)
• 作者: Zhang,Yue;Hansson,KennyM;Liu,Tao;Magnell,Kerstin;Huang,Yufeng;Carlson,NoelG;Kishore,BellamkondaK
• 通讯作者: Kishore,BellamkondaK

Genetic Deletion of P2Y2 Receptor Offers Long-Term (5 Months) Protection Against Lithium-Induced Polyuria, Natriuresis, Kaliuresis, and Collecting Duct Remodeling and Cell Proliferation.

P2Y2 受体的基因缺失可提供长期（5 个月）保护，防止锂引起的多尿、钠尿、钾尿以及集合管重塑和细胞增殖。

• DOI: 10.3389/fphys.2018.01765
• 发表时间: 2018
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Zhang,Yue;Riquier-Brison,Anne;Liu,Tao;Huang,Yufeng;Carlson,NoelG;Peti-Peterdi,János;Kishore,BellamkondaK
• 通讯作者: Kishore,BellamkondaK