The Molecular Basis of Nephrogenic Diabetes Insipidus
| Title: | The Molecular Basis of Nephrogenic Diabetes Insipidus |
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| Authors: | Oksche, Alexander; Rosenthal, Walter |
| Publisher: | Journal of Molecular Medicine |
| Date Published: | April 01, 1998 |
| Reference Number: | 162 |
Nephrogenic diabetes insipidus (NDI) is characterized by resistance of the kidney to the action of arginine-vasopressin (AVP); it may be due to genetic or acquired causes. Recent advances in molecular genetics have allowed the identification of the genes involved in congenital NDI. While inactivating mutations of the vasopressin V2 receptor are responsible for X-linked NDI, autosomal recessive NDI is caused by inactivating mutations of the vasopressin-regulated water channel aquaporin-2 (AQP-2). About 70 different mutations of the V2 receptor have been reported, most of them missense mutations. The functionally characterized mutants show a loss of function due to defects in their synthesis, processing, intracellular transport, AVP binding, or interaction with the G protein/adenylyl cyclase system. Thirteen different mutations of the AQP-2 gene have been reported. Functional studies of three AQP-2 mutations reveal impaired cellular routing as the main defect. The great number of different mutations with various functional defects hinders the development of a specific therapy. Gene therapy may, however, eventually become applicable to the congenital forms of NDI. At present all gene-therapeutic approaches lack safety and efficiency, which is of particular relevance in a disease that is treatable by an adequate water intake. The progress with regard to the molecular basis of antidiuresis contributes to the understanding of acquired forms of NDI on a molecular level. Recent data show that lithium dramatically reduces the expression of AQP-2. Likewise, hypokalemia reduces the expression of this water channel. The exact mechanisms leading to this reduced expression of AQP-2 remain to be determined.
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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)
In NDI, this entire sequence is interrupted, preventing the kidneys from reabsorbing water and concentrating urine. Hence, NDI's primary symptoms are polyuria (the chronic passage of large volumes of dilute urine) and polydipsia (chronic, excessive thirst). NDI may either be inherited, appearing as early as the first week of life, or acquired through metabolic disorders, kidney disease and use of drugs such as lithium and demeclocycline.
Researchers studying the molecular basis of NDI have identified mutations in the V2R gene and the AQP2 gene as causes of inherited NDI. About 90% of inherited NDI cases are due to mutations in the V2R gene, of which more than 70 different kinds have been reported. The remaining 10% are due to mutations in the AQP2 gene, of which more than 13 different kinds have been reported.
Mutations in genes can alter the structure of the proteins they produce. When a protein structure is altered, its ability to function may become altered as well. Researchers often study the structure-function relationships of proteins with a therapeutic goal in mind. In the case of NDI, the great number of different mutations and the different functional defects in the V2Rs and AQP2s they produce make the development of a specific genetic therapy for NDI challenging.
For example, the studies of V2R mutations that depict the structural and functional characteristics of the defective V2Rs show that, depending on the mutations, the V2Rs malfunction in different ways. The majority of the mutations prevent the V2R from reaching the cell membrane, where it must bind with AVP. Other V2R gene mutations result in V2Rs that are improperly folded, incomplete, unable to bind with AVP even though they can reach the cell surface, or unable to interact with the G protein/adenylyl cyclase system. And some defective V2Rs have a combination of these shortcomings.
Some of the V2Rs that cannot get to the cell surface are held in different places inside the cell, such as the endoplasmic reticulum or the golgi. Mutations in the AQP2 gene generally produce AQP2s that are unable to travel from their holding place in the endoplasmic reticulum; their inability to move to the cell surface makes it impossible for the cell membranes to become more water permeable. Researchers are developing clearer understandings of the locations of the structural defects, the specific amino acids involved and their location, and the resultant functional shortcomings. Gene therapy, therefore, may eventually become applicable to treating inherited NDI.
The V2R gene is carried on the X chromosome and its mode of inheritance is called X-linked recessive. A female carries the defective gene, but normally does not experience NDI symptoms. But if the defective gene is passed on to her son, he will. The AQP2 gene is carried on an autosomal (non-sex) chromosome, so both males and females can carry the gene and have NDI.
The clinical symptoms are the same whether inherited NDI is due to a mutation in the V2R gene or the AQP2 gene. However, there are ways to clinically distinguish which gene mutation is causing the disorder. Normally, an injection of a synthetic analog of AVP called DDAVP will cause the blood vessels to dilate. This leads to facial flush, a slight decrease in the main arterial pressure, and increase in certain blood factors associated with blood clotting. These responses are not seen in NDI patients with a V2R mutation, but they are seen in NDI patients with an AQP2 mutation.
There are forms of NDI which are acquired and not inherited. The use of lithium can cause NDI and is of particular interest as it is widely prescribed for certain psychological disorders such as manic depression. Lithium dramatically reduces the expression of AQP2 and causes pathological changes when accumulated in the cells of the kidney collecting duct. Recovery from lithium-induced NDI can be slow, and sometimes the damage is irreversible.
The primary management technique for NDI is ensuring increased water intake to balance the patient's polyuria. Secondary strategies include the use of one or a combination of such pharmacological agents such as thiazides, amiloride and cyclo-oxygenase inhibitors. (Thiazide should be used with care in lithium-induced NDI as it reduces lithium excretion. This sets up a potential for lithium toxicity.) At present, NDI can be treated but not cured. Genetic therapy may provide a possible cure in the future, provided research finds answers to many, as yet unresolved, molecular questions.