Involvement of Phosphodiesterases in Lithium-Induced Nephrogenic Diabetes Insipid

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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.