1998 Global Conference Proceeding
March 02 - 04, 1998
| Conference: | 1998 Global Conference |
|---|---|
| Title: | Vasopressin-Independent Regulation of Aquaporin-2 Protein |
| Author: | Ecelbarger, Ph.D., Carolyn |
| Institution: | Georgetown University |
Vasopressin-mediated regulation of collecting duct water permeability via changes in aquaporin expression and distribution has been well established. For aquaporin-2, this regulation involves both acute redistribution and chronic increases in abundance of the protein. Both modes of regulation increase the water permeability of the collecting duct. However, in certain clinical conditions, e.g., SIADH (syndrome of inappropriate antidiuretic hormone secretion), final urine concentration does not correlate with blood vasopressin levels. Furthermore, factors independent of vasopressin, e.g., prostaglandins have been shown to have substantial effects on final urine concentration.
Therefore, two groups of experiments were performed examining the role and regulation of kidney transporters in: 1) a rat model of SIADH in which rats were infused with dDAVP (1-deamino-[8-D-arginine]-vasopressin) and forced to consume a water load and 2) rats treated with cyclooygenase inhibitors in order to inhibit prostaglandin formation. In regard to the first set of experiments, escape from the anti-diuretic action of vasopressin occurred by the second day of water-loading. Vasopressin-escape rats had significantly reduced aquaporin-2 protein expression which extended to all 3 kidney regions: cortex, outer and inner medulla. Vasopressin-stimulated inner medullary collecting duct water permeability was reduced on average to 46% of control levels. Furthermore dDAVP-stimulated cAMP production as measured by radioimmunassay was significantly reduced in vasopressin escape rats suggesting that relative vasopressin resistance of collecting duct cells is responsible for the decrease in water permeability. Immunohistochemistry and differential centrifugation followed by immunoblotting, suggested that a redistribution of aquaporin-2 protein within the cell did not contribute to the escape phenomenon.
In the second set of experiments, non-specific inhibition of cyclooygenases, by indomethacin or diclofenac resulted in a dramatic increase in expression of the bumetanide-sensitive Na-K-2Cl cotransporter of the thick ascending limb as well as cellular redistribution of existing aquaporin-2 protein from intracellular sites into the apical plasma membrane. These observations support earlier physiological evidence for increased urine concentrating capacity with prostanglandin inhibition. However overall expression of aquaporin-2 protein was decreased with cyclooxygenase inhibition suggesting that acute and chronic regulation of aquaporin-2 by prostanglandins are by independent mechanisms.
By studying the mechanisms of vasopressin-independent regulation of collecting duct water permeability we may gain insight into the treatment of nephrogenic diabetes insipidus disorders, perhaps by developing therapies which by-pass vasopressin and the V2 receptor.
For the kidneys to concentrate urine properly, their cell membranes must be water permeable at the right times. Aquaporin-2 (AQP2), a water-transporting protein, ensures membrane permeability by responding to messages from the antidiuretic hormone, vasopressin, which cause AQP2 to become more plentiful and to redistribute throughout the kidney cells. But in some clinical conditions, urine concentration doesn't correlate with vasopressin levels. And other factors, e.g. prostaglandins, have been shown to have substantial effects on urine concentration.
Ecelbarger reports of experiments with rats, one of which showed that when rat collecting-ducts were made resistant to vasopressin's hormonal message, the rat kidneys expressed significantly less AQP2 and collecting-duct water permeability was reduced almost by half. Analyses showed the redistribution of AQP2 did not contribute to the lack of response to vasopressin. In the second experiment, rat prostaglandin formation was inhibited resulting in increased urine concentration capacity.
These findings suggest a new direction in research into therapies for nephrogenic diabetes insipidus (NDI) (which can result when messages from vasopressin can't be received due to mutations in receptors within the kidneys' collecting ducts) because they indicate collecting-duct water permeability can be regulated by means independent of vasopressin.