Involvement of Phosphodiesterases in Lithium-Induced Nephrogenic Diabetes Insipid

描述（由申请人提供）：肾源性尿崩症（NDI）的特点是在抗利尿激素、抗利尿激素存在的情况下，肾脏无法浓缩尿液，从而导致过量的稀尿。NDI分为两种类型：先天性NDI，这是一种x连锁基因突变；或者更常见的形式，获得性NDI，这通常是某些药物治疗的结果，包括双相情感障碍最常见和有效的治疗方法，锂。大约40%接受锂治疗的患者出现获得性NDI。锂诱导的NDI改变了参与尿浓度机制的转运蛋白。第二信使cAMP调节这些转运蛋白的功能。锂降低内髓集管cAMP水平，这可能解释了尿浓度失调的机制。另一种信使cGMP可以影响尿浓度，但锂如何影响cGMP信号尚不清楚。总磷酸二酯酶（PDE）活性，通过催化环核苷酸降解作为第二信使信号的调节开关，在长期锂治疗的大鼠中增加，但尚不清楚哪种特定的PDE受到影响。因此，我们假设锂离子介导的特定磷酸二酯酶的改变是导致锂离子诱导的NDI尿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.