Date Published: July 9, 2014
Publisher: Public Library of Science
Author(s): Jae H. Sim, Nathaniel J. Himmel, Sara K. Redd, Fadi E. Pulous, Richard T. Rogers, Lauren N. Black, Seongun M. Hong, Tobias N. von Bergen, Mitsi A. Blount, Eric Feraille.
Lithium, an effective antipsychotic, induces nephrogenic diabetes insipidus (NDI) in ∼40% of patients. The decreased capacity to concentrate urine is likely due to lithium acutely disrupting the cAMP pathway and chronically reducing urea transporter (UT-A1) and water channel (AQP2) expression in the inner medulla. Targeting an alternative signaling pathway, such as PKC-mediated signaling, may be an effective method of treating lithium-induced polyuria. PKC-alpha null mice (PKCα KO) and strain-matched wild type (WT) controls were treated with lithium for 0, 3 or 5 days. WT mice had increased urine output and lowered urine osmolality after 3 and 5 days of treatment whereas PKCα KO mice had no change in urine output or concentration. Western blot analysis revealed that AQP2 expression in medullary tissues was lowered after 3 and 5 days in WT mice; however, AQP2 was unchanged in PKCα KO. Similar results were observed with UT-A1 expression. Animals were also treated with lithium for 6 weeks. Lithium-treated WT mice had 19-fold increased urine output whereas treated PKCα KO animals had a 4-fold increase in output. AQP2 and UT-A1 expression was lowered in 6 week lithium-treated WT animals whereas in treated PKCα KO mice, AQP2 was only reduced by 2-fold and UT-A1 expression was unaffected. Urinary sodium, potassium and calcium were elevated in lithium-fed WT but not in lithium-fed PKCα KO mice. Our data show that ablation of PKCα preserves AQP2 and UT-A1 protein expression and localization in lithium-induced NDI, and prevents the development of the severe polyuria associated with lithium therapy.
Although lithium is an older antipsychotic, it still remains the most common treatment for bipolar disorder . Lithium also has beneficial effects in multiple other CNS disorders including stroke, multiple sclerosis, HIV-associated neurotoxicity and Huntington disease . Although lithium is effective at treating these and other CNS disorders, the drug is also known to be associated with renal, neurological and endocrine side effects . One of the renal side effects associated with lithium therapy is nephrogenic diabetes insipidus (NDI) which presents in approximately 40% of patients , . Affected patients present with polyuria, polydipsia, reduced capacity to produce concentrated urine and an inability to respond to vasopressin , . The advancing polyuria associated with lithium-acquired NDI may appear early in the treatment regimen and can be considered a contraindication to continued use. In many cases with chronic use, lithium-induced NDI cannot be reversed thus discontinuing therapy after a certain point may not be advantageous in reducing this side effect . Ensuing NDI is particularly problematic as the risk for acute renal failure is significantly elevated due to increased circumstance for acute lithium toxicity and/or dehydration from severe polydipsia/polyuria.
Although lithium is an older antipsychotic, it still remains a popular treatment for bipolar disorder and its therapeutic potential for other central nervous system (CNS) diseases is also gaining favor . The fraction of patients that develop lithium-induced NDI are more at risk to become dehydrated, increasing the risk of lithium toxicity , .