Lithium-induced Down regulation of Aquaporin-2 Water Channel Expression in Rat Kidney Medulla

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Title: Lithium-induced Down regulation of Aquaporin-2 Water Channel Expression in Rat Kidney Medulla
Authors: Marples, David; Christensen, Sten; Christensen, Erik Ilso; Ottosen, Peter D.; Nielsen, Soren
Publisher: Journal of Clinical Investigation
Date Published: April 01, 1995
Reference Number: 72
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Lithium, a widely used treatment for bipolar affective disorders, often causes nephrogenic diabetes insipidus. The effect of chronic lithium therapy on the expression of the vasopressin-regulated water channel Aquaporin-2 (AQP2) in rat kidney was examined. Membranes were prepared from inner medulla of one kidney from each rat, while the contralateral one was fixed for immunofluorescence and immunoelectronmicroscopy. Immunoblotting revealed that lithium treatment reduced AQP2 expression dramatically, to 31 +/- 8% after 10 d and to 4 +/- 1% after 25 d, coincident with development of severe polyuria. Immunofluorescence and immunogold quantitation confirmed the lithium-induced decrease in AQP2 expression (from 11.2 +/- 1.0 to 1.1 +/- 0.2 particles/microns 2). The downregulation was only partly reversed by return to lithium-free diet for 1 wk (40 +/- 8% of control). Furthermore, immunoblotting and immunogold quantitation revealed that 2 d of thirsting or 7 d of dDAVP treatment, in the continued presence of lithium, increased AQP2 expression by six- and threefold, respectively, coincident with increased urinary osmolality. Thirsting increased AQP2 immunolabeling mainly of vesicles, whereas dDAVP caused accumulation of AQP2 predominantly in the subapical region and plasma membrane. Thus, lithium causes marked downregulation of AQP2 expression, only partially reversed by cessation of therapy, thirsting or dDAVP treatment, consistent with clinical observations of slow recovery from lithium-induced urinary concentrating defects.
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This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)

Lithium is a drug that is widely administered for certain psychological disorders such as manic depression. A common side-effect of extended lithium use is nephrogenic diabetes insipidus (NDI), a disease characterized by the kidney's failure to concentrate urine in response to signals from the antidiuretic hormone, vasopressin (VP). Symptoms of NDI include chronic, excessive thirst (polydipsia) and chronic, excessive urination (polyuria). VP regulates the expression of aquaporin-2 (AQP2), a membrane protein that helps transport water across cell membranes, thus increasing the cell membranes' water permeability. Functional AQP2 is necessary for the urine concentrating process. AQP2 is located in the principal cells of the kidney collecting duct, mainly in the top portion of the cell membrane, and in little sacs inside the cell itself.


The molecular basis of lithium-induced NDI is not yet clearly understood. Marples, et al., used rats as subjects to investigate the effect of lithium use on the expression of AQP2. The researchers found that in rats fed lithium there was a sharp reduction in the amount of AQP2 expressed in the kidney collecting duct cells. These reduced numbers of AQP2 were accompanied by the development of severe polyuria.

This reduction in AQP2 was only partly reversed when the rats were returned to a lithium-free diet. One week after the experimental rats were taken off the lithium diet, their AQP2 expression remained well below the control group's. This is consistent with clinical observations that show patients take several weeks to regain their normal urinary concentrating ability after cessation of chronic lithium therapy. However, the researchers found that depriving lithium-fed rats of water for two days increased AQP2 expression in the little sacs within the kidney collecting duct cells six-fold, even though they were still continuing lithium. And administering a form of synthetic VP over a seven day period increased AQP2 expression three-fold. In both cases, these increases represented only a partial reversal of the lithium-induced reduction in AQP2. This partial increase was accompanied by a partial increase in the ability to concentrate urine.