Disordered Water Channel Expression and Distribution in Acquired Nephrogenic Diabetes Insipidus
| Title: | Disordered Water Channel Expression and Distribution in Acquired Nephrogenic Diabetes Insipidus |
|---|---|
| Authors: | Marples, David; Frokiaer, Jorgen; Knepper, Mark; Nielsen, Soren |
| Publisher: | Proceedings of the Association of American Physicians |
| Date Published: | October 01, 1998 |
| Reference Number: | 414 |
A series of recent studies have demonstrated that expression of aquaporin-2 (AQP2), the vasopressin-regulated water channel of the kidney collecting duct, is greatly reduced in acquired forms of nephrogenic diabetes insipidus (NDI). In some forms of NDI, there is also impaired delivery of these channels to the apical plasma membrane, where they permit water reabsorption from the urine. The combination of these factors is likely to underlie the urinary concentrating defect that defines these conditions. Direct infusion of vasopressin causes an increase in AQP2 expression, probably via a rise in cytosolic adenosine 3:5-cyclic phosphate, which also acts as the second messenger, triggering the delivery of AQP2 to the plasma membrane. However, it is clear from the studies described that there are also vasopressin-independent pathways that regulate the expression of AQP2, some of which appear to reflect intranephric changes, whereas others involve systemic signals. These studies also show that recovery of AQP2 expression, even after correction of the underlying condition, can be slow, consistent with the clinical observation that recovery of urinary-concentrating ability often takes weeks or months. An understanding of the cellular signals and mechanisms responsible for the decrease in AQP2 expression may make it possible to develop treatments for this common clinical problem.
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)
Normally, AVP will bind with vasopressin-2 receptors (V2Rs) located on the basolateral membranes of the principal cells of the kidney CDs. This initiates a molecular sequence wherein the enzyme, adenylyl cyclase (AdC), is stimulated to raise levels of cyclic adenosine monophosphate (cAMP) inside the principal cells. The cAMP then sends a message to proteins called aquaporin-2s (AQP2s) which directs them to transport to the apical membrane of the principal cells. Once the vesicles that have transported the AQP2s to the apical membrane are fused with it, the AQP2s are inserted into the membrane. There they act as channels through which much more water than usual can cross the apical membrane. This is how the kidneys are able to reabsorb the body water flowing through the kidney CDs.
When AVP withdraws from the cells, the AQP2s are retrieved from the apical membrane and the apical membrane returns to a state where very little water can cross it. Thus, AVP regulates the short-term translocation of AQP2s from inside the principal cell into the cell's apical membrane. In the longer term (over hours to days) AVP also triggers an increase in the number of AQP2s within the cell. Therefore, AVP controls both the rapid translocation of AQP2 to and from the apical membrane, and an increase in AQP2s during longer periods of dehydration.
NDI may be either inherited or acquired. Marples, et al., write on how acquired NDI affects both the expression (i.e. the number of) and the distribution (i.e. their location in either the inside of the cell or the cell's apical membrane) of AQP2s. The authors' draw their knowledge from the results of a series of experiments performed on rats with various forms of acquired NDI or disturbances to their AQP2 levels and distributions.
The authors found that a reduction of AQP2 (and sometimes an interference with its transport to the apical membrane) plays a fundamental role in the development of polyuria associated with many of the acquired forms of NDI. Their research confirmed that reduction in AQP2 numbers is the cause, not the consequence, of polyuria. Lithium-induced NDI, one of the most common forms of acquired NDI, induces a dramatic decrease of AQP2 expression paralleled by a progressive development of severe polyuria. Of the AQP2s that were expressed in the principal cells, very few got to the apical membrane.
Lithium has been shown to impair the production of cAMP in CD cells, and it is likely that reduced cAMP is, in part, responsible for reduced numbers of AQP2. cAMP, as you recall, increases in response to AVP activation of AdC.
Excessively low levels of plasma potassium (hypokalemia) or abnormally high levels of plasma calcium (hypercalcemia) are both capable of producing acquired NDI. Both conditions are associated with decreases in AQP2, though these conditions reduce AQP2 less than lithium. Accordingly, the polyuria associated with the former conditions is less severe. No matter the cause, once it is corrected it can take weeks or months for the system to build back the amount of AQP2s necessary for the water reabsorption urine concentration process to occur. Accordingly, it can take weeks or months before the accompanying polyuria is reversed.
Of interest is the fact that hypercalcemia, like lithium, interferes with the translocation of the AQP2s from the inner cell to the apical membrane as well as reducing AQP2s overall numbers. However, hypokalemia simply reduces AQP2 expression without interfering with its translocation to the apical membrane. This suggests that the molecular sequence that causes the reduction of AQP2 numbers is not the same sequence that directs AQP2 to the apical membrane.
There are likely to be one or more signals other than AVP that control AQP2 expression. The researchers observed that restricting rats from water for two days greatly increases the number of AQP2s found in the principal cells, even more than AVP does. It was known that the AVP-induced rise in cAMP levels resulted in a rise in the number of AQP2s as well as their translocation to the apical membrane. However, the authors found that changes in AQP2 expression can occur independently of the action of AVP. The sources of the change can be both systemic (e.g. dehydration) and local (e.g. pressure changes or metabolic changes in kidney tissues). Marples, et al., speculate that the other signals influencing AQP2 expression might also use cAMP. Thus, cAMP may be a common factor in more than one of the sequences that alter AQP2 expression.
The authors indicate that a clearer understanding of the mechanisms involved in AQP2 expression and translocation will provide more effective treatment of conditions such as acquired NDI.