Pathogenesis and Treatment of Autosomal-Dominant Nephrogenic Diabetes Insipidus Caused by an Aquaporin 2 Mutation
|Title:||Pathogenesis and Treatment of Autosomal-Dominant Nephrogenic Diabetes Insipidus Caused by an Aquaporin 2 Mutation|
|Authors:||Sohara, Eisei; Rai, Tatemitsu; Yang, Sung-Sen; Uchida, Keiko; Nitta, Kosaku; Horita, Shigeru; Ohno, Mayuko; Harada, Akihiro; Sasaki, Sei; Uchida, Shinichi|
|Publisher:||Proceedings of the National Academy of Sciences of the U.S.A|
|Date Published:||September 19, 2006|
You may, however, read this article at the Proceedings of the National Academy of Sciences of the U.S.A. website.
To return to this page, use your "back" key.
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)
The aquaporin 2 protein, in response to a molecular sequence initiated when the hormone, vasopressin (AVP) binds with the vasopressin 2 receptor (V2R) on the membrane of the kidney collecting duct principal cells, moves from the cell interior to the top (apical) section of the cell membrane. Once embedded in the apical section of the cell membrane, it acts as a channel through which water can flow into the cell. AQP2, then, plays a vital role in the kidney’s ability to concentrate urine. Mutations in the AQP2 gene can result in NDI. There are two types of NDI caused by AQP2 mutations: autosomal-recessive (AR-NDI) and autosomal-dominant NDI (AD-NDI). In the former, both pair of chromosomes carry a defective AQP2 gene. In the latter, only one of the chromosome pair carries a defective AQP2 gene. Of the two, AD-NDI has less severe NDI symptoms.
Sohara, et al., had previously identified three different AQP2 mutations that resulted in AD-NDI. Each of these AQP2 mutations resulted in AQP2s that had different amino acids than normal in a section of the AQP2 called the C-terminus. The research team had used laboratory cell cultures to determine how AD-NDI mutants could cause NDI. The results were highly suggestive, but they could not be used to accurately model how these mutant AQP2 behaved in living bodies because the levels of normal and mutant AQP2 in the cell cultures did not correspond to the proportions in the bodies of those with AD-NDI.
To better understand the mechanics of how the mutant AQP2s in AD-NDI actually cause the disease in living systems, Sohara, et al., developed a line of mice with AD-NDI. To do this, they created a AQP2 protein that was part mouse and part human, the human part being the C-terminus with an AD-NDI mutation. They injected this into the mice. The resulting mouse line exhibited the same mix of normal and mutant AQP2 proteins as do humans with AD-NDI. Further, these mice reacted to dehydration and had similar urine concentration and urine volume as did humans with AD-NDI. Thus, this mouse line was a good model with which to examine the mechanics of AD-NDI and to test treatment of it.
Upon examination, the researchers found that the mutant AQP2 in their mice did not go to the apical section of the cell membranes of the principal cells in the kidney collecting duct. Instead, they went to the bottom and sides of the membrane, a section called the basolateral membrane. Not only that, the mutant AQP2s would bind with the normal AQP2s and take them to the basolateral membrane.
The research team tested several types of phosphodiesterase (PDE) inhibitors – PDE 3, 4 & 5 - to see if they could increase the concentration of urine and reduce urine volume in the AD-NDI mice. Of the three tested, PDE4, also called rolipram, was able to increase the urine concentration ability of the AD-NDI mice. Rolipram increased the number of AQP2 traveling to the apical membrane. It also increased the levels of cyclic adenosine monophosphate (cAMP) in the principal cells. This increase in cAMP correlated well with the increase in urine concentration. cAMP is required in the molecular sequence that results in urine concentration because it activates protein Kinase A (PKA). PKA adds a phosphate group (in a process called phosphorylation) to the AQP2. This helps AQP2 travel to the apical membrane. The researchers also found that rolipram increased the phosphorylation of AQP2.
In sum, this research group established a mouse line that serves as a model to investigate AD-NDI, discovered that mutant AQP2s in AD-NDI travel to the basolateral membrane instead of the apical membrane, discovered that the mutants bind with normal AQP2s in the cell and misdirect them to the basolateral membrane, and found that PDE4 may be useful in treating AD-NDI.