Lithium (Li) salts are widely used for treating bipolar disorders. However, ~ 40% of the patients develop nephrogenic diabetes insipidus (NDI) with severe polyuria and polydipsia. Moreover, for 10-20% of the patients, Li treatment results in chronic kidney disease, which may eventually lead to end-stage renal disease and/or the discontinuation of lithium treatment even if no efficient mood-controlling alternative is available.
Animal studies have shown that the toxic effects of Li are linked to ENaC mediated entry and accumulation of Li in principal cells. Li-induced polyuria is associated with reduced AQP2 expression and a cellular remodeling of the collecting duct resulting in reduced fraction of principal cells relative to type A intercalated cells. The low fraction of AQP2-expressing principal cells and reduced transcription in the remaining principal cells contribute to the pathophysiology of Li-NDI. The exact mechanisms behind the cellular remodeling and the AQP2 downregulation are still subject to multiple studies. Phosphorylation of AQP2 by MAPK may be involved. The loss of principal cells may be due to extrusion of the cells by loss of their cellular attachment to the basement membrane, which involves changes in cellular contact proteins. Cellular plasticity of the collecting duct cells may also involved. Current pharmacological options in Li-NDI have only modest effect and there is a need for identification of new drug targets. Similar, it is important to know whether the molecular mechanisms identified in animals are applicable to human kidney.