Role of Aquaporin Water Channels in Kidney and Lung
| Title: | Role of Aquaporin Water Channels in Kidney and Lung |
|---|---|
| Author: | Verkman, Alan S. |
| Publisher: | American Journal of Medicine and Science |
| Date Published: | November 01, 1998 |
| Reference Number: | 200 |
Several aquaporin-type water channels are expressed in mammalian kidney and lung: AQP1 in lung microvessels and kidney proximal tubule, thin descending limb of Henle, and vasa recta; AQP2 in apical membrane of collecting duct epithelium; AQP3 and AQP4 in basolateral membranes of airway and collecting duct epithelium; and AQP5 in alveolar epithelium. Novel quantitative fluorescence methods demonstrated very high water permeabilities of the alveolar epithelial and endothelial barriers, and moderately high water permeability across distal airways. In the kidney, water permeability is high in proximal tubule and thin descending limb of Henle, and regulated by vasopressin in collecting duct. The author's laboratory has studied the role of aquaporins in organ physiology using transgenic knockout mice lacking specific aquaporins. AQP1 null mice are mildly growth-retarded, manifest a severe urinary concentrating defect, and have reduced water permeability between airspace and capillary compartments. AQP4 null mice appear normal grossly except for a mild defect in maximum urinary concentrating ability. AQP2-deficient humans have hereditary non-X-linked nephrogenic diabetes insipidus (NDI). In transfected mammalian cells, many NDI-causing AQP2 mutants are retained in the endoplasmic reticulum. The author's laboratory has found that "chemical chaperones," that is, small compounds that promote protein folding in vitro, are able to correct defective AQP2 trafficking in cell culture models. The transenic mouse and mammalian cell models are thus beginning to provide clues about the role of aquaporins in 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)
AQP2 is located in the principal cells of the kidney collecting ducts (CDs). There it resides in tiny sacs called water channel vesicles (WCVs) beneath the apical membrane. (If you imagine the principal cell as an upright rectangle and the rectangle's perimeter as the cell membrane, the bottom and sides are the basolateral membrane, and the top is the apical membrane.)
AQP2 is regulated by the antidiuretic hormone, arginine vasopressin (AVP). When AVP binds with its receptors located on the basolateral membranes of the principal cells, it sends a signal to the WCVs. The WCVs are induced to travel to and fuse with the apical membrane. Upon fusion, the AQP2s are inserted into the apical membrane. This membrane normally does not allow much water to flow through it, but once the AQP2s are inserted into it, there is a dramatic increase in the amount of water that crosses the cell membrane. The apical membrane's increased water permeability allows the kidney to reabsorb the body water flowing through its CDs. What liquid is left behind is concentrated urine that is voided. Thus, the AVP-regulated AQP2 plays a major role in helping the kidney maintain body water balance by increasing the CD principal cell's water permeability.
Nephrogenic diabetes insipidus (NDI) is a disorder characterized by the kidney's inability to respond to AVP. As a result, the NDI patient cannot reabsorb the body water flowing through his kidney CDs. The NDI patient experiences polydipsia (chronic, extreme thirst) and polyuria (chronic passage of large volumes of urine).
NDI may either be acquired or inherited. The acquired form of NDI may occur as a result of, among other things, long-term lithium use, blockage of the ureters (the fibromuscular tubes that connect the bladder to the kidneys), degenerative kidney disease, and excessive calcium in the blood. Acquired NDI is generally associated with a reduction in the number of AQP2s expressed in the kidney CD principal cells.
Though the vast majority of inherited NDI cases are the result of mutations in the vasopressin-2 receptor (V2R) gene, more than 15 different mutations in human AQP2 gene have been identified in patients with inherited NDI who have normal V2R genes. This means that AQP2 gene mutations can cause NDI. Generally, the AQP2 gene mutations in NDI patients result in AQP2s that cannot perform their function due to one or more of the following defects: decreased function, low numbers (i.e. due to a decreased rate of synthesis or an increased rate of degradation, there aren't enough AQP2s expressed in the cell to do their job), and the inability of the AQP2 to travel to the apical membrane due to having irregular shapes or not being able to interact properly with the structures that guide it to the membrane.
Researchers are amassing detailed knowledge of the structural and functional mechanics of AQP2. They are doing this by studying the relationship between the normal AQP2 structure and its ability to function and comparing it to the defective AQP2 structure/function relationship. This knowledge may result in genetic therapies for NDI patients.
Verkman has experimented with "chemical chaperones" and AQP2. Chemical chaperones are small molecules, such as glycerol, that help proteins fold into their proper shape in laboratory cell cultures. Many AQP2 mutations result in AQP2s being unable to fold into their normal shape. The author selected three mutated AQP2 genes, the defective AQP2s from which are improperly folded. Because they are improperly folded, they are not allowed out of the endoplasmic reticulum, a kind of finishing and review station within the cell.
Cells containing the mutated genes were grown in a medium containing glycerol for 48 hours. This produced a nearly complete redistribution of the AQP2s generated from the mutant genes from the ER to the membranes. Additionally, these cells became water-permeable which indicate the AQP2s were functioning normally.
However, the concentration of glycerol needed to help the AQP2s fold into the proper shape was very high. Verkman experimented with other chemical chaperones such as dimethyl sulfoxide, D2O and trimethyamine oxide (TMAO). He found that TMAO was also effective in getting defective AQP2s properly folded and out of the endoplasmic reticulum. This work suggests that chemical chaperones might be useful for treatment of protein folding defects in the kidney.