Aquaporins: From Physiology to Nephrogenic Diabetes Insipidus

Title: Aquaporins: From Physiology to Nephrogenic Diabetes Insipidus
Authors: Knoers, Nine; van Lieburg, Angenita; Monnens, Leo A.H.; van Oost, Bernard A.; Deen, Peter M.T.; van Os, Carel
Publisher: Advances in Nephrology
Date Published: January 01, 1996
Reference Number: 41
Water movement across cell membranes is a process of central importance at the most fundamental level. Transport of water into and out of cells occurs, for instance, during digestion, respiration, circulation, sweating, and urine formation. In most cells, water movement occurs by simple diffusion through the membrane lipid matrix. Certain cell types, however, show an exceptionally high water permeability, which suggest the involvement of channel- or pore-mediated transport.1, 2 Such cells include but are not restricted to proximal tubule epithelial cells in the kidney, erythrocytes, and selected cells in vasopressin-sensitive tissues such as the mammalian kidney-collecting duct and amphibian urinary bladder. Although the physiologic aspects of channel-mediated water transport in these cell types have been described accurately, the molecular basis of water channels remained elusive for decades. Significant progress in the research of water transport occurred recently with discovery of the so-called aquaporins, a family of intrinsic membrane proteins that function as water-selective channels in the plasma membranes of cells of many water-transporting tissues.3-6

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)

Water movement across cell membranes is a vital and necessary physiologic process. Water moves in and out of most cells by diffusing through fat in the cells' outer membranes. But some cells allow so much water to permeate in and out of them that researchers predicted these cells would have some sort of channel in their membranes that, at the proper time, would open up to allow the easy and full entry and exit of water through the cell membrane. Later research identified such a channel, dubbed water channels, and described their physiologic function. More recent research uncovered and explained the molecular basis of water channels.

Water channels were discovered to be proteins. The water channels in red blood cell membranes are water-selective. That is, they only let water and small nonelectrolytes pass through them. Water channels were also found in the cell coverings (epithelia) of the kidneys. This made sense since the epithelia of the kidney tubules (the little tubes in the kidneys through which fluid passes) has more water flow through it than the epithelia of any other body part. The degree to which water can flow across the epithelia of kidney collecting ducts depends on the presence of the antidiuretic hormone, arginine vasopressin (AVP). That is, the hormone, AVP, regulates kidney collecting duct water permeability.

To work, AVP must bind to specific receptors in the collecting duct cells. These vasopressin (V2) receptors are coupled to the enzyme, adenylate cyclase. AVP cannot occupy a V2 receptor unless a metabolic process takes place within the cell where the V2 receptor lives. This process involves a stimulatory G protein, activation of adenylate cyclase, and an increase of an important metabolic regulator called cAMP. This process results in the top of the cell membrane, which is water tight in the absence of AVP, becoming highly water permeable. This increased water permeability is the beginning of another process which leads to the formation of concentrated urine.

Scientists generally believe that the increase in the top of the cell's water permeability results from the shuttling of small sacs of liquid containing preformed water channels to the cell top membrane. The small sacs, stimulated by AVP, fuse with the cell's top membrane and the water channel flows from sac to membrane. When the AVP is removed, the water channels are retrieved from the membrane.

Biophysical and physiologic experiments, then, had shown the existence of these water-transporting proteins (i.e., water channels). But the molecular identity of these water channels remained unclear until the more recent set of research breakthroughs which located a protein the mass of which was 28 kilodaltons (kD). The discoverers of this protein called it CHIP28 and demonstrated it was indeed a molecular water channel. That is, it serves as a channel for water only and excludes small ions and neutral solutes. This set the stage for the discovery of aquaporins: the family of water channel proteins found in plants and animals. CHIP 28 was renamed aquaporin-1 (AQP1).

AQP1 was found to be an important route for water movement in many tissues. Human red blood cells and kidney tubules contain nearly adult levels of AQP1 at birth. However, no AQP1 was found in the kidneys' collecting ducts, and they are very water permeable. What was found in the collecting ducts was another aquaporin, AQP2, that resides exclusively in the kidney collecting ducts. It, too, is probably AVP regulated (though this has not been proven absolutely) and is shuttled to and from the top of cell membranes where it increases the cell's water flow.

The third member of the aquaporin family is the protein AQP3. It is found in the kidney and gastrointestinal tract and differs from the others in that it transports nonionic molecules such as urea and glycerol in addition to water. At present, whether AQP3 is regulated by AVP or not is unknown. Another AQP was discovered, though it differs from the rest in that the presence of mercury compounds does not inhibit its function as it does the other AQPs. This AQP is named mercurial insensitive water channel (MIWC). MIWC is found in cells that do not express AQP1 and it is probable that it is crucial for, among other things, the urinary concentrating mechanism.

The most recent addition to the AQP family is called WCH3. It is found exclusively in mammalian kidneys. It may be AVP regulated. It is not yet known where in the cell membrane it is located or whether or not it transports water only.

Since AQP1 is distributed so widely throughout the body, it was assumed that mutations of AQP1 would result in serious complications. However, this is not the case; people with mutated AQP1 showed none of the expected blood, kidney, eye, lung, gastrointestinal or neurologic dysfunction expected. Scientists think the body has other mechanisms that compensate for nonfunctioning AQP1.

However, mutations in AQP2 are associated with forms of nephrogenic diabetes insipidus (NDI), a disease characterized by an inability of the kidneys to concentrate urine in response to the hormonal message of AVP. Congenital NDI is present from birth and can manifest its symptoms as early as the first week of life. These symptoms include excessive thirst and urination, dehydration, irritability, vomiting, poor feeding and weight gain, and fever. If not treated early, repeated episodes of dehydration could lead to mental retardation, failure to thrive, and death.

Congenital NDI is inherited, like any other thing is inherited, by means of a gene. Scientists found that V2 receptor gene mutations were consistent with the appearance of NDI. The V2 receptor gene is located in region Xq28 on the X chromosome (a sex chromosome). If a gene is located on an X chromosome it is a recessive trait. Numerous studies confirmed the correspondence of a mutated V2 receptor gene and congenital NDI. And since functional V2 receptors are necessary to properly concentrate urine, the V2 receptor gene NDI link was much researched and congenital NDI was considered to be an X-linked inheritable disorder.

However, this finding could not explain all the ways in which NDI was inherited. If it was always an X-linked phenomenon then only males would be subject to NDI. Yet, though NDI is primarily expressed in males, females also can express it. Researchers knew then that NDI could also be caused by a mutation of a gene carried by an autosomal (non-sex) chromosome.

Researchers discovered that congenital NDI could also be caused by a mutation in the AQP2 gene. AQP2 is the vasopressin-regulated water channel in the kidney that is essential for the concentration of urine in response to vasopressin. When it is nonfunctional due to mutation, the kidney collecting duct can neither transport water nor concentrate urine as it should. There is no difference between the NDI symptoms caused by either V2R or AQP2 mutations and researchers should be aware of both forms when diagnosing families affected by NDI.

A few NDI patients who do not have mutations in either the V2 receptor gene or the AQP2 gene are known, but the source of the mutations that gave rise to their NDI is not. Research on these patients might help to identify other proteins essential in helping the kidneys properly concentrate urine in response to vasopressin.