The Aquaporin Family of Water Channel Proteins in Clinical Medicine

Title: The Aquaporin Family of Water Channel Proteins in Clinical Medicine
Authors: Lee, M. Douglas; King, Landon S.; Agre, MD, Peter
Publisher: Medicine (Baltimore)
Date Published: May 01, 1997
Reference Number: 174
The aquaporins are a family of membrane channel proteins that serve as selective pores through which water crosses the plasma membranes of many human tissues and cell types. The sites where aquaporins are expressed implicate these proteins in renal water reabsorption, cerebrospinal fluid secretion and reabsorption, generation of pulmonary secretions, aqueous humor secretion and reabsorption, lacrimation, and multiple other physiologic processes. Determination of the aquaporin gene sequences and their chromosomal locations has provided insight into the structure and pathophysiologic roles of these proteins, and primary and secondary involvement of aquaporins is becoming apparent in diverse clinical disorders. Aquaporin-1 (AQP1) is expressed in multiple tissues including red blood cells, and the Colton blood group antigens represent a polymorphism on the AQP1 protein. AQP2 is restricted to renal collecting ducts and has been linked to congenital nephrogenic diabetes insipidus in humans and to lithium-induced nephrogenic diabetes insipidus and fluid retention from congestive heart failure in rat models. Congenital cataracts result from mutations in the mouse gene encoding the lens homolog Aqp0 (Mip). The present understanding of aquaporin physiology is still incomplete; identification of additional members of the aquaporin family will affect future studies of multiple disorders of water distribution throughout the body. In some tissues, the aquaporins may participate in the transepithelial movement of fluid without being rate limiting, so aquaporins may be involved in clinical disorders without being causative. As outlined in this review, our challenge is to identify disease states in which aquaporins are involved, to define the aquaporins' roles mechanistically, and to search for ways to exploit this information therapeutically.

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)

Aquaporins are a family of membrane proteins that allow water to cross the plasma membranes of a wide variety of human tissues and cell types. Their existence was postulated when scientists reasoned that the amount of water that traveled across certain membranes of tissues and cells was much more than could be accounted for by osmotic diffusion alone. Subsequently the proteins that were responsible for this increased water flow were discovered and named aquaporins (AQPs). They are found in mammals, plants, bacteria and yeast.
There are, at present, six different aquaporins that have been found in mammals: aquaporins 0 - 5. Each has a unique pattern of tissue expression with minimal overlap in distribution. The site of each AQP expression is believed to reflect a site where rapid transfer of water occurs in response to pressure signals.

There have been many studies to identify the molecular structure of AQP1. It is thought to live within the cell membrane, the thin layer of tissue that encircles the cell separating the inside of the cell from the outside. If you imagine the AQP1 as a string of beads, most of it lies folded within the membrane in six clumps called transmembrane regions 1 - 6. Part of the AQP snakes outside the membrane to form extracellular loops A and C. Part of it snakes out of the membrane into the cell to form intracellular loop D. Two loops, loop B and loop E, form within the membrane. And the two ends of the AQP1, the amino-terminal and the carboxy-terminal, sit within the cell itself with intracellular loop D. Loops B and E are thought to overlap, forming a single pathway for water molecules to pass through in single file.

Recently, the chromosomal locations for the AQPs have been identified. AQP 1, 3 and 4 genes are all located on different chromosomes, whereas AQP 0, 2, and 5 are located on chromosome 12.

As mentioned, AQPs are expressed in many major organs, notably the kidney, lung, brain and eyes. However, since readers at this site are most interested in nephrogenic diabetes insipidus (NDI), we will focus on that section of Lee, et al.'s, article which focuses on the kidney.

AQPs help the kidney maintain body salt and water balance. The primary functional units of the kidney are nephrons. There are about one million of them in each kidney and they consist of a filter called a glomerulus that is attached to a small tube called a tubule through which the filtered body fluid flows to the kidney collecting duct. That portion of the tubule closest to the glomerulus is called the proximal tubule; that portion farthest away from the glomerulus is called the distal tubule. Between these two segments of the tubule lies a segment called the loop of Henle which has both an ascending and descending limb.

Of the 200 liters of glomerular filtrate produced daily by an average adult, around 80% is reabsorbed by the proximal tubule in the descending limb of the loop of Henle, a site where AQP1 is abundant.

The 20% of glomerular filtrate that is not reabsorbed by the proximal tubule and the descending limb of the loop of Henle may be reabsorbed through the kidney collecting duct when AQP2 is stimulated by the antidiuretic hormone, vasopressin (VP). When VP binds with the vasopressin-2 receptor, it sets off a cascade of events which signals AQP2s to shuttle to the apex of the principal cells of the kidney collecting duct. Once there, they significantly increase the water permeability of the cells, allowing the filtrate to be reabsorbed. This also allows the kidney to concentrate urine.

Though water enters the apex of the principal cells of the kidney collecting duct thanks to AQP2, it exits through the base and sides of these cells via AQP3 in most levels of the collecting duct, or through AQP4 in the kidneys inner medulla (i.e. the kidney's innermost part). Then the water is absorbed back into the vascular system through AQP1 that is present in the layer of cells that line the vasa recta.

Because AQPs play such an important role in helping the kidney concentrate urine and maintain water and salt balance, it could be expected that if they were not functioning properly, they could form the molecular basis of disease. Oddly enough, the exceedingly small number of people lacking AQP1s do not manifest any related disorder. However, people lacking AQP2 manifest a severe form of nephrogenic diabetes insipidus (NDI), a disorder characterized by the kidney's inability to reabsorb water and concentrate urine in response to VP. AQP2 is found only in the principal cells of the kidney collecting duct and is the AQP responsible for maximal water concentration by the kidney. Thus it is essential for the normal concentrating ability of the human kidney.

People can be born with NDI due to defective or absent AQP2 due to mutations in their AQP gene. People can also acquire NDI, notably through intake of the drug, lithium, which is often prescribed for certain psychological disorders. In tests on rats, lithium has been found to dramatically reduce AQP2 expression. Humans on lithium therapy often develop NDI, and most cease to express NDI symptoms after being taken off the drug.