Development of Lithium-Induced Nephrogenic Diabetes Insipidus is Dissociated from Adenylyl Cyclase Activity

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Title: Development of Lithium-Induced Nephrogenic Diabetes Insipidus is Dissociated from Adenylyl Cyclase Activity
Authors: Li, Yuedan; Shaw, Stephen; Kamsteeg, Erik-Jan; Vandewalle, Alain; Deen, Peter M.T.
Publisher: Journal of the American Society of Nephrology
Date Published: April 01, 2006
Reference Number: 702
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Abstract • Article • Translation
In antidiuresis, vasopressin (AVP) occupation of V2 receptors in renal collecting ducts activates adenylyl cyclase, resulting in increased intracellular cAMP levels, which activates protein kinase A (PKA). PKA phosphorylates both the cAMP responsive element binding protein, which induces aquaporin-2 (AQP2) transcription, and AQP2, which then is translocated to the apical membrane, allowing urine concentration. Lithium treatment often causes nephrogenic diabetes insipidus (NDI), which coincides with decreased AQP2 expression and which generally is ascribed to reduced adenylyl cyclase activity. However, the underlying mechanism by which lithium causes NDI is poorly understood. This study demonstrated that the mouse cortical collecting duct mpkCCD(c14) cells are a good model; the deamino-8 D-arginine vasopressin (dDAVP)-induced endogenous AQP2 expression and plasma membrane localization was time-dependently reduced by treatment with clinically relevant lithium concentrations. Lithium did not affect AQP2 stability but decreased its mRNA levels. Surprising, the effect of lithium was cAMP independent; it did not alter AVP-stimulated cAMP production or PKA-dependent phosphorylation of AQP2 or cAMP responsive element binding protein. In vivo, kidney tissue of rats with lithium-induced NDI indeed generated less dDAVP-induced cAMP than that of controls, but this could be due to elevated blood AVP levels in rats with lithium-induced NDI. Indeed, Brattleboro rats, which lack endogenous AVP, with clamped blood dDAVP levels, showed no difference in dDAVP-generated cAMP generation between kidneys of rats with lithium-induced NDI and control rats. In conclusion, the first proper cell model to study lithium-induced NDI was developed, and it was demonstrated that the lithium-induced downregulation of AQP2 and development of NDI occur independent of adenylyl cyclase activity in vitro and in vivo.
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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)

When the antidiuretic hormone, arginine vasopressin (AVP), binds with the vasopressin 2 receptor (V2R) stationed on the membrane of the principal cells of the kidney collecting duct, the following chemical sequence occurs: the enzyme adenylyl cyclase is activated; this in turn raises the intracellular levels of cyclic adenosine monophosphate (cAMP). The increased cAMP levels activate protein kinase A (PKA). The PKA adds a phosphate group to (i.e., phosphorylates) the aquaporin-2 (AQP2) water channel protein. This initiates the movement of AQP2 to the apical (top) section of the collecting duct principal cell membranes. PKA also phosphorylates the cAMP responsive element binding protein (CREB). This increases the synthesis of AQP2.

It is through this chemical sequence that the kidneys are able to reabsorb body water and concentrate urine in order to maintain body water balance.

Lithium is one of the most popular drugs used to treat bipolar disorders. Yet, it causes NDI in 30 – 40% of the people who use it. NDI is a disorder of the kidney’s water concentrating abilities. Conventional wisdom posits that lithium results in NDI because it reduces AQP2 levels by causing a reduction in adenylyl cyclase activity.

However, the mechanism by which lithium causes NDI is poorly understood. Li, et al., sought to rectify this by first developing a proper cell model to study lithium-induced NDI. Then they used that model to conduct a series of careful experiments with the proper cell culture. Finally, they conducted experiments with living rats so that they could explore the mechanics of lithium induced NDI via both cell culture and living models. The research team developed the proper cell model by using a mouse cortical collecting duct cell line (mpkCCD). This cell line could express AQP2 when stimulated with AVP. The team found that:

  1. Lithium reduces the number of AQP2s expressed in the cell culture in a time and dose dependent manner. That is, the longer the cell culture was exposed to lithium, and the larger the dose of lithium, the fewer number of AQP2s were expressed.
  2. Lithium treatment results in AQP2s staying within the cell and away from the cell membrane where it must be in order to perform its job. This effect increases in a time and dose dependent manner.
  3. Lithium decreases AQP2 expression not by instigating the cell to destroy it, but by decreasing AQP2 mRNA levels.
  4. Lithium does not decrease adenylyl cyclase activity in the mpkCCD cells. Nor does it decrease it in the principal collecting duct cells of living rats.

Li, et al.’s, experiments indicated that the actual mechanism by which lithium can cause NDI is through reducing the numbers of AQP2s in the kidney collecting duct principal cells by decreasing AQP2 mRNA levels. The pathway through which it does this does not interfere with AVP stimulated cAMP production or PKA-dependent phosphorylation of AQP2 or CREB.