2000 Global Researcher Conference Proceeding
March 10 - 12, 2000
| Conference: | 2000 Global Researcher Conference |
|---|---|
| Title: | Prostaglandins as Stimulants of AQP2 Expression: a Possible Future Treatment for NDI? |
| Authors: | Marples, David; Baggaley, Erin |
| Institution: | University of Leeds |
In nephrogenic diabetes insipidus, the kidney is unable to reabsorb water normally from the urine in response to the antidiuretic hormone (ADH) vasopressin. This is usually due to an inability to increase collecting duct water permeability, because of a defect in either the V2 receptors that bind ADH, or the AQP2 water channels that mediate the increase in water permeability. In hereditary NDI, these defects reflect mutations in the protein which make it non-functional, while in acquired forms of NDI there is an inhibition of the normal cellular function. In some cases, this means that the receptor fails to send the normal “second messenger” to induce transfer of water channels to the apical plasma membrane of the cells, while in others there is a decrease in the number of water channels available for transfer. In either case, the consequence is that the increase in water permeability of the collecting duct is greatly reduced.
The acute shuttling of AQP2 should not be thought of as an “all or none” phenomenon, with the water channels either in the plasma membrane or in the vesicles, but as an equilibrium, with the fraction which are in the plasma membrane being regulated by the level of ADH in the blood. Changes in the total amount of AQP2 present in the cells will alter the permeability of the collecting duct at any given level of ADH. Therefore, treatments which can increase AQP2 expression are likely to increase collecting duct permeability, and hence decrease polyuria. Such treatments include vasopressin itself, but this will not work in NDI, since the tissue is more or less unresponsive to it. Dehydration also provides a potent stimulus, which is at least partly independent of the effect of vasopressin.
We have indirect evidence indicating that increased prostaglandin production underlies the dehydration-induced increase in AQP2 expression, since non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit prostaglandin production, decrease AQP2 levels, and can prevent the dehydration-induced increase in expression. NSAIDs inhibit cyclooxygenase (COX), the enzyme that is the rate-limiting step in the production of prostaglandins. An increase in COX-2, the inducible form of the enzyme, seems to be important in the effect of dehydration, since the COX-2 specific NSAID meloxicam reduces AQP2 expression in dehydrated, but not in water-loaded, rats. Interestingly, oral administration of an E-series prostaglandin (the major type produced in the renal inner medulla) did not stimulate AQP2 expression.
With the assistance of a pump-priming grant from the NDI Foundation, we will shortly determine the effect of infusing PGE2 and PGI2 (prostacyclin) analogues, to see if we can increase AQP2 expression. If successful, this might, in the longer term, provide the foundation of a treatment to relieve the polyuria of NDI.
Aquaporin 2 (AQP2) water channels play an important role in the kidney’s ability to concentrate urine: it allows water to pass through the kidney collecting duct into the interior of the kidney. In NDI this ability is interrupted, due to a mutation in either the vasopressin-2 receptor (V2R) gene or the AQP2 gene. When signaled by a sequence of events set in motion by V2R, AQP2 shuttles from the interior of the cell to the apical cell membrane, making it water permeable.
Marples and Baggaley point out that it is helpful to remember that AQP2 is not at any one time either in the cell membrane or in the cell interior. Rather, AQP2 is always both in the cell interior and the cell membrane. The extent to which it is in each is dependent on the amount of arginine vasopressin (AVP) in the blood. Thus, changes in the total amount of AQP2 in the cells will affect the amount of water that can pass through the collecting duct; the more AQP2 in the cell, the more likely more water will be able to pass through.
Therefore, Marples and Baggaley suggest that treatments which can increase the number of AQP2 channels in the cell are likely to increase the amount of water that can pass through the collecting duct into the kidney interior, even in the absence of vasopressin. This would improve the kidney’s ability to concentrate urine. The researchers are beginning research to determine if the infusion of prostaglandin 2 (PGE 2) and prostacyclin (PGI2) analogues will increase the number of AQP2 channels in the cells.