Physiology and Pathophysiology of Aquaporins
| Title: | Physiology and Pathophysiology of Aquaporins |
|---|---|
| Authors: | van Lieburg, Angenita; Mulders, Sabine M.; van Os, Carel; Deen, Peter M.T.; Knoers, Nine; Monnens, Leo A.H. |
| Publisher: | European Journal of Clinical Investigation |
| Date Published: | December 01, 1996 |
| Reference Number: | 251 |
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 their review, Mulders, et al., present the latest information on AQPs 0-5, but as this site is dedicated to information relating specifically to nephrogenic diabetes insipidus (NDI), we will present what the authors have to report on AQP2, the aquaporin known to be associated with NDI.
AQP2s are located in the principal cells of the kidney collecting duct (CD). They reside within little sacs called vesicles. These vesicles rest in their holding site beneath the apical membrane. (Picture the principal CD cell as an upright rectangle; the section of membrane running across the top of the cell is the apical membrane.)
Researchers propose the following structure for AQP2. It is a string of 271 amino acids. Portions of the string are clumped together within the membrane, forming six separate coiled clumps called transmembrane helices 1-6. Part of the string snakes outside the membrane to form three curves called extracellular loops A, C and E. Part of it snakes inside the cell to form two curves called intracellular loops B and D. Both ends of the AQP2 are inside the cell with intracellular loops B and D. (You can look at a diagram of AQP2 here.)
AQP2 is regulated by the antidiuretic hormone, arginine vasopressin (AVP). This means it does not perform its job until signaled to do so by AVP. When AVP binds with one of its receptors, the vasopressin-2 receptor (V2R), it sends a signal via a molecular sequence that notifies the AQP2-bearing vesicles to leave their holding site beneath the apical membrane. They travel to the apical membrane and fuse with it. It is at this point that the AQP2s within the vesicles insert themselves into the apical membranes to make them more water permeable.
When AVP removes itself from the V2R, vesicles retrieve the AQP2s from the membrane and cycle back to the holding places beneath the apical membrane. There is evidence that individual AQP2s can perform this cyclic shuttling to the apical membrane and back again three times before they are dissolved.
The importance of AQP2 to the health of the body lies in the fact that by making the kidney CD principal cells more water permeable, the kidney is able to reabsorb most of the water passing through the CD. This allows the kidney to balance body water and concentrate urine.
It is not completely clear what molecular machinery is required to get the AQP2 bearing vesicles to and from the apical membrane. But it is known that two vesicle-associated membrane proteins (VAMPs), VAMP-2/synaptobrevin and cellubrevin, are located in the same intracellular vesicles as is AQP2. VAMPs are known to play a role in guiding other vesicles to and from membranes, and researchers suspect they play the same role in the AQP2-bearing vesicles. Other researchers indicate that a Rab3-like protein, which appears to be located in or near AQP2-bearing vesicles may help guide the AQP2-bearing vesicles to the apical membrane.
Also, AQP2 contains two leucine amino acid residues side by side in its carboxy terminus (the tail end of the protein) that may be important for the AQP2 to be brought back inside the cell from the cell membrane.
Nephrogenic diabetes insipidus (NDI) is a disorder characterized by the kidneys inability to reabsorb water passing through the kidney collecting duct or to concentrate urine. As a result, the NDI patient voids large volumes of dilute urine and drinks large volumes of liquid to replenish body water lost through urination.
Mutations in the AQP2 gene produce defective AQP2s incapable of performing their function. If AQP2 cannot make the kidney CD cell apical membranes more water permeable, then the kidney cannot reabsorb water flowing through the CD or concentrate urine. The result is NDI.
To date, the AQP2 mutations discovered by researchers result in the AQP2s not being able to transport from their holding site to the apical membrane. The AQP2 gene is carried on chromosome 12, which means both males and females can inherit this type of NDI. This type of congenital NDI is called autosomal-recessive because the child must inherit a mutated AQP2 gene from both parents to express NDI. But recently, Bichet, et al., reported an autosomal-dominant form of autosomal NDI, which means only one parent had a mutated AQP2 gene and that was sufficient for the child to manifest NDI.
NDI can also be acquired as a result of another systemic disease, a physical obstruction or long-term use of specific prescription drugs such as lithium. Lithium is associated with down-regulation of AQP2s (i.e. the reduction the number of AQP2s expressed). Low blood levels of potassium, experiential nephrotic syndrome, chronic kidney failure and the release of blockage in the ureters, the fibromuscular tubes that carry urine from the kidneys to the bladder, also can result in NDI. AQP2 plays a role in several of the acquired forms of NDI, as illustrated by the down-regulation of AQP2s as a result of long-term lithium use.