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Trendsetters
Division of Nephrology N-8, 501 Smyth Road Ottawa, ON, Canada K1H 8L6
In this section we feature some of the latest and most striking new findings in physiology, interpreting the term "physiology" in its broadest sense. In each instance, an effort will be made to place the new findings in perspective.
Heinz Valtin
Editor, TRENDSETTERS
Most of the elements that enable mammalian kidneys to concentrate urine are now well known and accepted: through countercurrent multiplication, the loops of Henle generate a hypertonic renal medullary interstitium, which causes osmotic water flow out of collecting ducts having apical membranes that have been rendered highly permeable to water by vasopressin-regulated water channels known as aquaporin 2 (AQP2). At least three other water channels are found in mammalian kidneys that are not regulated by vasopressin: aquaporin 1 (AQP1), located in apical and basolateral membranes of proximal tubules and thin descending limbs of Henle, as well as in vasa recta, and aquaporins 3 and 4 (AQP3 and AQP4), which are located in the basolateral membrane of collecting duct principal cells (unlike the vasopressin-regulated AQP2 channels, which reside in the apical membranes of these cells). Although localization of these other channels is consistent with previously identified transport properties of the given structures, and although the essentiality of high water permeability in structures other than collecting ducts to the urine-concentrating mechanism has been recognized, the specific contributions of these other, apparently unregulated, membrane proteins (AQP1, AQP3, and AQP4) are now being explored through the use of gene knockout models.
Chou and co-workers (1) studied the role of AQP4 by measuring the osmotic water permeability of isolated, perfused inner medullary collecting ducts (IMCDs) from homozygous AQP4 knockout mice that express no AQP4 protein. They found that vasopressin-stimulated transepithelial water permeability was fourfold lower in the knockout than in the wild-type mice. That this difference was due specifically to the absence of AQP4 was demonstrated by Northern and immunoblot analyses showing that the message and expression patterns for AQP1, AQP2, and AQP3 in the kidneys of knockout mice were not different from those of wild-type mice. Furthermore, absence of AQP4 was shown not to affect AQP3 function. Thus AQP4 appears to be the major water channel in the basolateral membrane of IMCDs. However, despite the rather striking decrease in water permeability in vitro, the knockout mice exhibited only a mild defect of urinary concentration following water deprivation (mean urine osmolality ~2,600 vs. 3,300 mosmol/kgH20 in wild-type mice). This finding reemphasizes the critical importance of bulk water reabsorption in cortical and outer medullary collecting ducts (where AQP4 is expressed to a lesser degree) to the excretion of concentrated urine.
The results with AQP1 knockout mice are in contrast to the mild concentrating defect in AQP4 knockout mice. Ma and colleagues (2) found that when the AQP1 membrane protein is eliminated (but AQP2, AQP3, and AQP4 remain) the mice were unable to maintain water balance during dehydration, even when given the vasopressin analog, desamino-d-arginine vasopressin; the body weight of these mice fell by 35%, their serum osmolality rose to over 500 mosmol/kgH20, and their urine osmolality did not increase over levels observed on ad libitum water intake (~600 mosmol/kgH20). Schnermann et al. (3) found that osmotic water permeability in isolated, perfused proximal tubules from AQP1 knockout mice was reduced by almost 80% (to values not different from diffusion through lipid bilayers) and that proximal "isosmotic" reabsorption in vivo and in vitro was reduced by ~50%. These results emphasize the importance of a high transcellular water permeability of proximal tubules and demonstrate that this permeability is due to AQP1 channels. It was expected that the reduced proximal fluid reabsorption would result in increased fluid delivery to collecting ducts (which would reduce urine concentration), but this prediction was not confirmed in this study (3). More detailed experiments, including water permeability measurements of thin descending limbs and vasa recta (where AQP1 is also expressed), will no doubt elucidate the major tubular site(s) responsible for the concentrating defect in this model.
Thus the information provided by gene knockout animal experiments are helping us to further define the role of so-called constitutive membrane water channel proteins (which, to date, do not appear to be physiologically regulated) in urine concentration. Future experiments, using both single and multiple channel knockouts, as well as other disease models, may further refine our views.
References
| Occasionally, the Editor of the Trendsetters section invites contributions from the authors of published scientific articles that have been identified as being of special interest. All précis to Trendsetters are by invitation only. |
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