Involvement of Phosphodiesterases in Lithium-Induced Nephrogenic Diabetes Insipid

磷酸二酯酶与锂诱导的肾性糖尿病无味的关系

• 批准号: 8096251
• 负责人: Mitsi A Blount
• 金额: $ 7.75万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8096251
• 关键词: Affect; Animal Model; Bipolar Disorder; Chronic; Chronic Kidney Failure; Cyclic AMP; Cyclic GMP; Cyclic Nucleotides; Development; Diabetes Mellitus; Duct (organ) structure; Enzymes; Family; Fibrosis; Gene Mutation; Hypercalcemia; Investigation; Kidney; Kidney Failure; Lead; Link; Lithium; Mediating; Metabolic; Methods; Monitor; Mus; Nephrogenic Diabetes Insipidus; Nephrotoxic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phosphodiesterase Inhibitors; Physiological; Polyuria; Property; Protein Isoforms; Proteins; Rattus; Role; Second Messenger Systems; Signal Transduction; Therapeutic Effect; Urine; Vasopressins; common treatment; effective therapy; functional restoration; inhibitor/antagonist; novel; phosphoric diester hydrolase; prevent; response; second messenger; trafficking; urea transporter; water channel

DESCRIPTION (provided by applicant): Nephrogenic diabetes insipidus (NDI) is characterized by the inability of the kidney to concentrate urine in the presence of the antidiuretic hormone, vasopressin, thereby leading to excessive volumes of dilute urine. NDI is classified into two types: congenital NDI, which is an X-linked genetic mutation; or the more commonly observed form, acquired NDI, which is often an effect of certain drug therapies including the most common and effective treatment for bipolar disorder, lithium. Approximately 40% of patients receiving lithium present with acquired NDI. Lithium-induced NDI alters the transporters involved in the urine concentration mechanism. The second messenger cAMP regulates the function of these transporters. Lithium reduces cAMP levels in the inner medullary collecting duct which may explain the dysregulation of the urine concentration mechanism. Another second messenger, cGMP, can affect urine concentration however it is unknown how lithium affects cGMP signaling. Total phosphodiesterase (PDE) activity, which acts as a regulatory switch for second messenger signaling by catalyzing the degradation of cyclic nucleotides, is increased in rats chronically treated with lithium but it is unclear which specific PDE is affected. We therefore hypothesize that lithium-meditated alterations of specific phosphodiesterases are responsible for the disruption of the urine concentration mechanism that occurs in lithium-induced NDI PUBLIC HEALTH RELEVANCE: Development of acquired nephrogenic diabetes insipidus (NDI) after lithium use is due to a decrease in the key transporters involved in urine concentration. Intracellular levels of cAMP and cGMP, which are altered with chronic lithium treatment, influence functional properties of these transporters. We hypothesize that lithium-meditated alterations of specific phosphodiesterases, enzymes that regulate intracellular cAMP and cGMP levels, are responsible for the disruption of the urine concentration mechanism that occurs in lithium-induced NDI.

描述（由申请人提供）：肾源性尿崩症（NDI）的特征是在抗利尿激素血管加压素存在的情况下，肾脏无法浓缩尿液，从而导致稀释尿液体积过多。NDI分为两种类型：先天性NDI，这是一种X连锁基因突变;或更常见的形式，获得性NDI，这通常是某些药物治疗的效果，包括最常见和有效的治疗双相情感障碍，锂。大约40%接受锂治疗的患者存在获得性NDI。锂诱导的NDI改变了参与尿液浓缩机制的转运蛋白。第二信使cAMP调节这些转运蛋白的功能。锂降低了内髓集合管中的cAMP水平，这可以解释尿浓度机制的失调。另一种第二信使cGMP可以影响尿液浓度，但目前尚不清楚锂如何影响cGMP信号传导。总磷酸二酯酶（PDE）的活性，作为第二信使信号的调节开关，催化环核苷酸的降解，增加了长期治疗的大鼠锂，但目前还不清楚具体的PDE受到影响。因此，我们假设锂介导的特定磷酸二酯酶的改变是导致锂诱导的NDI中发生的尿浓缩机制中断的原因。 公共卫生相关性：使用锂后发生获得性肾源性尿崩症（NDI）是由于参与尿液浓度的关键转运蛋白减少。cAMP和cGMP的细胞内水平，这是改变与慢性锂处理，影响这些转运蛋白的功能特性。我们推测，锂介导的特定磷酸二酯酶的改变，调节细胞内cAMP和cGMP水平的酶，是负责在锂诱导的NDI发生的尿液浓缩机制的破坏。