Pathophysiology of the Aquaporin Water Channels
| Title: | Pathophysiology of the Aquaporin Water Channels |
|---|---|
| Authors: | King, Landon S.; Agre, MD, Peter |
| Publisher: | Annual Review of Physiology |
| Date Published: | 1996 |
| Reference Number: | 44 |
Discovery of aquaporin water channel proteins has provided insight into the molecular mechanism of membrane water permeability. The distribution of known mammalian aquaporins predicts roles in physiology and disease. Aquaporin-1 mediates proximal tubule fluid reabsorption, secretion of aqueous humor and cerebrospinal fluid, and lung water homeostasis. Aquaporin-2 mediates vasopressin-dependent renal collecting duct water permeability; mutations or downregulation can cause nephrogenic diabetes insipidus. Aquaporin-3 in the basolateral membrane of the collecting duct provides an exit pathway for reabsorbed water. Aquaporin-4 is abundant in brain and probably participates in reabsorption of cerebrospinal fluid, osmoregulation, and regulation of brain edema. Aquaporin-5 mediates fluid secretion in salivary and lacrimal glands and is abundant in alveolar epithelium of the lung. Specific regulation of membrane water permeability will likely prove important to understanding edema formation and fluid balance in both normal physiology and disease.
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)
At present, there are five known members of the aquaporin family: aquaporin 1,2, 3, 4, and 5. The aquaporins are distributed throughout the mammalian body, with some showing a greater affinity for certain areas in the body than others. For example, aquaporin 1 (AQP1) is distributed throughout red blood cells, parts of the little filtration tubes in the kidney, the blood vessels in the innermost part of the kidney (the renal medulla), parts of the eye, brain, lung, and cell layers that line the bones, heart, and muscle. AQP2 is distributed throughout the kidneys' collecting ducts. AQP3 is located in the base and sides of membrane cells in the kidneys' collecting ducts, trachea, the far end of the colon and cells at the surface of the brain. AQP4 is found mostly in the brain, parts of the kidney, and lung. AQP5 is distributed in the cells of tear ducts, salivary glands, the cell lining of the cornea, and certain cells in the lung. Researchers gain clues as to the role AQPs play in the health and disease of different parts of the body by how they are distributed.
AQPs sit within the cell membrane, the thin, permeable wall that separates the inside of the cell from the outside. Some AQPs sit in the bottom and sides of the cell membrane. Others, such as AQP2, sit in the top of the membrane. AQPs are more active at certain times than others, and scientists are currently researching what regulates the level of aquaporin activity. There is evidence suggesting that naturally occurring hormones may regulate the expression of AQP1. AQP2, 4 and 5 may, in part, be regulated by a metabolic process called phosphorylation. In their article, King and Agre present detailed information on the distribution of the five known AQPs and scientific speculation on their function in normal physiology and disease. Since readers are primarily interested in nephrogenic diabetes insipidus (NDI), we will focus only on the information the authors present on AQP2, as dysfunctions of AQP2, alone among the known aquaporins, are known to result in NDI.
AQP2 is the predominant water channel protein in the principal cells of the kidney collecting duct. It is sensitive to the antidiuretic hormone, arginine vasopressin (AVP). AVP starts a process which shuttles the AQP2 to the top of the cell membrane where it serves to increase the cell's water permeability so the collecting duct can reabsorb bodily fluid filtered by other parts of the kidney.
When AQP2 is deficient or dysfunctional, NDI can result. Mutant AQP2s often cannot perform their function as water channels. That is, they cannot make the cell membranes of the kidney collecting duct more permeable to water, so the collecting duct cannot reabsorb water. AQP2 mutations can either cause a structural change in the AQP2 or prevent it from shuttling to its work site in the cell membrane. The result is that the afflicted person excretes large volumes of dilute urine, a hallmark of NDI.
NDI can either be inherited or acquired. One way NDI can be acquired is through the use of lithium, which is used to treat psychological disorders. Lithium use is known to cause defective urine concentrations in 50% of lithium users and to cause polyuria (excessive urination) in 20% of the users. Polyuria is a hallmark of NDI. It is thought that lithium dramatically reduces the amount of AQP2 expressed in the system. If there is not enough AQP2 (as in the case of NDI), then the AQP2 cannot do its job. Researchers now think that introducing synthetic AQP2 into the specific areas where it is lacking could be an effective strategy for treating NDI and other disorders resulting from a deficit of AQP2.
The discovery of aquaporin water channels is a major step to understanding the molecular basis of water movement across biological membranes in both normal physiology and disease. Scientists are just beginning to plumb the depths of AQPs, and further research could be of great benefit in the treatment of diseases associated with impaired water transport.