Pathophysiology of Aquaporin-2 in Water Balance Disorders
| Title: | Pathophysiology of Aquaporin-2 in Water Balance Disorders |
|---|---|
| Authors: | Knepper, Mark; Nielsen, Soren; Marples, David; Frokiaer, Jorgen |
| Publisher: | American Journal of Medicine and Science |
| Date Published: | November 01, 1998 |
| Reference Number: | 202 |
The recent identification of aquaporin water channel proteins has provided detailed information about the molecular basis for transepithelial water transport. At least five aquaporins have been identified in the kidney; they have provided detailed molecular insight into the fundamental physiology of water balance. This article focuses primarily on the physiology and pathophysiologic significance of the vasopressin-regulated water channel aquaporin-2 (AQP2) in a number of conditions where body water balance is disturbed. AQP2 is regulated by vasopressin by both short- and long-term mechanisms. Acutely, vasopressin induces exocytic insertion of AQP2 into the apical plasma membrane to increase collecting duct water reabsorption. Moreover, long-term regulation of body water balance is achieved by changes in total collecting duct levels of AQP2. Recent studies have documented that both vasopressin and vasopressin-independent regulation play important roles in this. In conditions with acquired nephrogenic diabetes insipidus (eg, lithium treatment, hypokalemia, postobstructive polyuria), AQP2 expression and targeting have been found to be markedly reduced, providing an explanation for the polyuria and the inability to concentrate urine associated with these conditions. Conversely, in conditions with water retention (eg, heart failure, pregnancy), it has been shown that AQP2 levels and plasma membrane targeting are increased. Continued analysis of aquaporins is providing detailed molecular insight into the physiology and pathophysiology of water balance disorders.
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)
AQP2s sit in tiny sacs called water channel vesicles (WCVs) beneath the principal cell's apical membrane. (If you imagine the principal cell as an upright triangle and the perimeter as the cell membrane, the bottom and sides are called the basolateral membranes, and the top is the apical membrane. Normally, the apical membrane does not let water permeate through it.) When the antidiuretic hormone, arginine vasopressin, binds with the vasopressin-2 receptor on the basolateral membranes of the principal cell, it initiates a molecular sequence which induces the WCVs to travel to and fuse with the apical membrane. Upon fusion, the AQP2s are inserted into the apical membrane. Once inserted, the AQP2s act as channels through which water flows across the cell membrane, thus dramatically increasing the apical membrane's level of water permeability.
When the apical membrane's water permeability is increased, the kidney is able to reabsorb the body water flowing through the CDs. The liquid that is not reabsorbed is concentrated urine which is later voided. Thus, AQP2 plays a vital part in the kidney's water regulating system.
AQP2 is regulated both by short-term and long-term mechanisms. Short-term regulation has been described in the preceding paragraphs: AQP2, in quick response to AVP, transports to the apical membrane and increases its water permeability. Long-term regulation of AQP2 refers to processes that either increase or decrease the number of AQP2s in the cell over a longer time period. The long-term regulatory mechanisms are not precisely known, but likely involve the AQP2 protein synthesis mechanisms and the ability of AVP to increase the level of the metabolic regulator, cyclic adenosine monophosphate (cAMP). Experiments with rats show that dehydration caused by withholding water for two days significantly increased the number of AQP2s present in their CD principal cells. Thus, dehydration could also be a long-term regulator of AQP2.
Nephrogenic diabetes insipidus (NDI) is a disease characterized by the kidney's inability to respond to the antidiuretic message of AVP. The kidney is unable to reabsorb the body water flowing through the kidney CDs. It is unable to concentrate urine. As a result, the NDI patient experiences polyuria (chronic passage of large volumes of urine) and polydipsia (chronic, excessive thirst).
NDI may either be acquired or inherited. Acquired NDI can be caused by a number of things such as:
- long-term lithium use,
- abnormally low levels of potassium,
- abnormally high levels of calcium,
- obstruction of the urinary tract,
- or a low-protein diet.
But, no matter the cause, acquired NDI is characterized by a downregulation of AQP2s. That is, there are fewer AQP2s than needed to increase the apical membrane's water permeability. And if the apical membrane's water permeability is not increased by AQP2s, then the kidney cannot reabsorb the body water flowing through the CDs, nor can it concentrate urine.
There are two causes of inherited NDI: mutations in the vasopressin-2 receptor (V2R) gene, and mutations in the AQP2 gene. The vast majority of inherited NDI is caused by mutations of the V2R gene. These mutations result in defective V2Rs which do not bind with AVP, so the molecular sequence which signals AQP2s to travel to and insert themselves into the apical membrane cannot take place. AQP2 gene mutations result in AQP2s that cannot get to the apical membrane. Both types of gene mutations do not allow the AQP2-mediated increase in apical membrane water permeability necessary for body water reabsorption and urine concentration.
There are diseases such as congestive heart failure that are associated with inappropriate increases in AQP2 resulting in excessive reabsorption of body water and water retention. Experiments inducing cirrhosis of the liver in rats have produced different results: a downregulation of AQP2s when the cirrhosis was induced by binding the rats' bile ducts; and an increase in levels of AQP2s when the cirrhosis was induced by a 12-week period of twice-weekly injections of carbon tetrachloride and olive oil. The authors speculate that the latter method produced a more severe case of cirrhosis which resulted in the up-regulation of AQP2s. In the less severe case, the body could still try and compensate for potential excessive water retention by down-regulating the amount of AQP2s in the CD principal cells. Lower numbers of AQP2 are also associated with laboratory-induced degenerative kidney disease in rats. The down-regulation here may also occur as a compensatory response to reduce further extracellular fluid volume expansion.
Vasopressin escape is a condition where vasopressin is not released into the blood stream as usual in order to prevent water intoxication. Two groups of rats were injected with DDAVP, a synthetic derivative of AVP. One group was forced to ingest water; the other could drink if they wished. The former group was found to generate much lower numbers of AQP2. This down-regulation of AQP2 may represent a physiologically appropriate way to reduce the capacity to reabsorb water. Since both rats had equal amounts of DDAVP in them, this study suggests that there is a way to signal AQP2 other than AVP.
The authors conclude by stating that the discovery and analysis of aquaporins have provided detailed molecular insight into the physiology and pathophysiology of water balance and water balance disorders.