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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Small Research Grants (R03)
Project #
Application #
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Emory University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Hoban, Carol A; Black, Lauren N; Ordas, Ronald J et al. (2015) Vasopressin regulation of multisite phosphorylation of UT-A1 in the inner medullary collecting duct. Am J Physiol Renal Physiol 308:F49-55
Sands, Jeff M; Blount, Mitsi A (2014) Genes and proteins of urea transporters. Subcell Biochem 73:45-63
Sim, Jae H; Himmel, Nathaniel J; Redd, Sara K et al. (2014) Absence of PKC-alpha attenuates lithium-induced nephrogenic diabetes insipidus. PLoS One 9:e101753
Klein, Janet D; Blount, Mitsi A; Sands, Jeff M (2012) Molecular mechanisms of urea transport in health and disease. Pflugers Arch 464:561-72