Phosphodiesterases in Lithium-Induced Nephrogenic Diabetes Insipidus

说明(申请人提供)：肾源性尿崩症(NDI)的特征是肾脏在抗利尿激素血管加压素存在的情况下无法浓缩尿液，从而导致过多的稀释尿量。NDI分为两种类型：先天性NDI，这是一种X连锁的基因突变；或更常见的观察形式，获得性NDI，这通常是某些药物疗法的效果，包括治疗双相情感障碍最常见和有效的疗法-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体。第二信使阵营调节这些转运蛋白的功能。锂降低内髓集合管的cAMP水平，这可能解释了尿液浓度机制的失调。另一种信使cGMP可以影响尿液浓度，但目前尚不清楚锂是如何影响cGMP信号的。总磷酸二酯酶(PDE)活性是第二信使信号的调节开关，通过催化环核苷酸的降解而发挥调节作用。在长期服用锂的大鼠中，总磷酸二酯酶(PDE)的活性增加，但尚不清楚哪种特定的PDE受到影响。因此，我们假设锂离子引起的特定磷酸二酯酶的改变是锂离子诱导的NDI中尿液浓度机制被破坏的原因。 公共卫生相关性：使用锂后获得性肾源性尿崩症(NDI)的发生是由于与尿液浓度有关的关键转运体的减少。细胞内cAMP和cGMP水平随着慢性锂治疗的改变而改变，影响这些转运体的功能特性。我们假设，锂诱导的NDI中特定的磷酸二酯酶(调节细胞内cAMP和cGMP水平的酶)的变化是导致尿液浓度机制中断的原因。

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.