The Aquaporin Family of Water Channels in Kidney: an Update on Physiology and Pathophysiology of Aquaporin-2
| Title: | The Aquaporin Family of Water Channels in Kidney: an Update on Physiology and Pathophysiology of Aquaporin-2 |
|---|---|
| Authors: | Knepper, Mark; Marples, David; Nielsen, Soren; Frokiaer, Jorgen; Agre, MD, Peter |
| Publisher: | Kidney International |
| Date Published: | June 01, 1996 |
| Reference Number: | 197 |
The long-standing problem of membrane water transport has been advanced by the recognition of a new family of water transport proteins, the "aquaporins" [1-3]. Not surprisingly, water transport is a major process in kidney physiology, and the biology of aquaporins is most thoroughly understood in that organ. We reviewed in detail the status of aquaporins in the kidney only one year ago [4], but the subsequent progress has dictated the need for an update. This seems especially appropriate in honor of the 100th birthday of Homer Smith, the pioneer whose foresight initiated this field.
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 general, aquaporins (there are currently four different AQPs: AQP1, AQP2, AQP3, and AQP4) share a similar structure. Think of an AQP as a beaded string (the beads are amino acids). Most of the AQP lies within the cell membrane in six folded clumps called transmembrane domains 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 the intracellular loops. (You can look at a diagram of AQP2 here.) To act as a channel for water to pass through, transmembranes 1 and 6 swing together to form one cluster consisting of transmembrane domains 1, 2 and 6, and one cluster of transmembrane domains 3, 5 and 4. In this position, intracellular loop B positions itself with extracellular loop E in such a way as to form a pathway through which water flows.
The main working unit of the kidney is the nephron. There are about a million of them in each kidney. Each consists of a filter, called a glomerulus, and a tube called a tubule. The tubule is divided into different sections, each with a different function. The section nearest the glomerulus is called the proximal tubule; the section furthest from the glomerulus is called the distal tubule. In-between these is the loop of Henle, so curved as to have an ascending limb (with a thin and a thick portion) and a descending limb (with a thick and a thin portion). The tubule enters into a kidney collecting duct through which the kidney reabsorbs water passing through and concentrates urine.
In the kidney, AQP1 appears in cells in the proximal tubule and the thin descending limb of Henle, both of which display high levels of osmotic water permeability. It is located in the apex, sides and base of the membranes of the cells. The proximal tubules reabsorb approximately 50 to 60% of the fluid passing through the glomeruli, and AQP1 plays a large role in letting them do this. Oddly enough, mutations of the AQP1 gene which produce defective AQP1s seem to have no effect on the water permeability of the proximal tubule and thin descending limb.
In the kidney, AQP2s appear exclusively in the principal cells of the kidney collecting duct. The predominant location of the AQP2s is in the apical cell membrane and in little sacs called vesicles that cluster just beneath the top of the cell membrane.
AQP2 is the predominant water channel in the kidney collecting duct. It is shuttled in its holding vesicles from just beneath the apical membrane to the apical membrane itself. There it is inserted into the membrane to act as a channel through which water flows. The antidiuretic hormone, vasopressin (VP) is what signals AQP2 to make its trip to the apical membrane.
Research has revealed that water permeability of the collecting duct is primarily regulated, in both the short- and long-term, by VP and AQP2. In the short-term, VP signals AQP2 to insert itself in the collecting duct membranes to increase water reabsorption. In the long-term, the number of AQP2s are largely dependent on the concentration of circulating VP.
Mutations of the AQP2 gene produce faulty AQP2s incapable of increasing the collecting duct principal cells' water permeability. This results in nephrogenic diabetes insipidus (NDI), a disorder characterized by the inability of the kidney to concentrate urine or reabsorb water through the collecting duct. The primary symptoms of NDI are polyuria (passage of large volumes of urine) and polydipsia (chronic, excessive thirst).
AQP3, located in the base and sides of collecting duct principal cells, transport other molecules, such as urea, in addition to water. Though not definitely demonstrated, it is likely that AQP3 may function in a way to allow water and urea to exit from the base and sides of the cell. AQP4 is found in the brain where it apparently functions as a receptor responsible for the secretion of VP.
The authors conclude by stating that continued study of AQPs will continue to clarify the biomechanics of water balance and water balance disorders.