Physiology and Pathophysiology of the Aquaporin-2 Water Channel
|Title:||Physiology and Pathophysiology of the Aquaporin-2 Water Channel|
|Authors:||Knoers, Nine; Deen, Peter M.T.|
|Publisher:||Current Opinion in Nephrology and Hypertension|
|Date Published:||January 01, 1998|
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)
What follows in this process is not entirely clear, but it leads to water-transporting proteins called aquaporin-2 (AQP2 proteins) traveling from their holding place inside the CD cell to the apical membrane of the cell. Once at the membrane, the AQP2s insert themselves into it. This greatly increases the amount of water that can flow through the membrane. And this is how the kidney is able to reabsorb body water flowing through the kidney CDs. If any part of this sequence defaults, then the AQP2s cannot increase the water permeability of the CD cells and the kidney is unable to balance body water or concentrate urine. Thus, it is essential that AQP2s can get to the CD apical membranes to increase their water permeability.
The body regulates CD cell apical water permeability in two ways. In the short term, it uses AVP to increase membrane permeability as described above. (When AVP absents itself from the cell surface, the AQP2s exit the apical membrane, returning it to its much less water permeable state.) Long term regulation of apical cell water permeability involves the body's adaptation to an extended period of dehydration. The body responds to this by increasing levels of AQP2 mRNA and protein levels so that there are more AQP2s generally available to increase cell membrane permeability. Unlike short term regulation by AVP, long term regulation in CD apical membrane permeability via increase in AQP2 expression is not rapidly reversible.
AQP2s reside in little sacs called vesicles inside the CD cell. Researchers are trying to determine by what means these vesicles get from the ER to the cell membrane. At present, there is speculation that a vesicle targeting protein, VAMP-2, that has been found in the AQP2-bearing vesicles may guide the vesicles to the membrane and then bind with a protein called syntaxin-4 that is expressed in the apical membrane of CD cells.
AQP2s have been found to be associated both in diseases involving increased water reabsorption and decreased water reabsorption. Examples of the former are congestive heart failure, liver cirrhosis, the syndrome of inappropriate secretion of AVP and nephrotic syndrome. Patients with these diseases develop an increased water retention, leading to a large excess of extracellular fluid. In rats with severe congestive heart failure, researchers found highly increased AQP2 protein mRNA levels, mostly localized in the apical membranes. Since AQP2 increases apical cell water permeability, allowing the kidney to reabsorb body water, the increased levels of AQP2 could allow increases in the amount of body water retained in the body. Researchers concluded that the increases in both short and long term expression of AQP2 was a direct effect of increased levels of AVP in the blood.
Nephrogenic diabetes insipidus (NDI) is an example of a disease involving decreased water reabsorption. NDI may be either acquired or inherited and AQP2 may be involved in some types of both forms. In rats with lithium-induced NDI researchers have noted extensively reduced expression of AQP2. Sometimes patients with both of their ureters (the tubes that bring urine from the kidneys to the bladder) develop NDI, and this too is associated with decreased levels of AQP2.
Mutations in the AQP2 gene have been shown to be a cause of one form of congenital NDI. Some of the mutations render the AQP2 proteins non-functional, some leave it functional, but unable to reach the apical membrane because they are, because of misfolding, stuck in their site of synthesis, the endoplasmic reticulum. In any case, affected AQP2s are unable to make the CD apical cell membranes more water permeable and body water that should be reabsorbed in the body is voided as dilute urine, leading to a critical water balance disorder.
Thus, the regulation of AQP2 is critically important in water balance disorders. And it is hoped that further research will lead to better avenues for management and cure of such disorders.