1999 European Regional Conference Proceeding
May 12 - 16, 1999
| Conference: | 1999 European Regional Conference |
|---|---|
| Title: | Obstructive nephropathy -- a common acquired condition of nephrogenic diabetes insipidus |
| Author: | Frokiaer, Jorgen |
| Institution: | The Water and Salt Research Center, University of Aarhus |
Urinary tract obstruction is a common disorder seen in both children and adults, which, depending on the location and the degree of obstruction, may cause serious deterioration of renal function, including inability to produce a concentrated urine. The recent identification of aquaporin water channel proteins have provided detailed information about the molecular basis for the development of body water balance disorders. Aquaporin-2 (AQP2) is the vasopressin regulated water channel of the kidney collecting duct, which has been shown to be critically involved in numerous pathophysiological conditions associated with nephrogenic diabetes insipidus. Release of bilateral ureteral obstruction (BUO) results in polyuria, and impairment of urinary concentrating capacity. After release of unilateral ureteral obstruction (UUO), GFR is reduced and the fractional excretion of both sodium and water is increased. Consequently, both BUO and UUO is characterized by a marked impairment in the ability of the postobstructed kidney to concentrate urine, which is resistant to vasopressin treatment.
To examine whether this urinary concentrating defect was related to changes in AQP2 expression, we used a rat model in which both ureters were reversibly obstructed. After obstruction for 24 hours, AQP2 expression was reduced to 26±8%, supporting the view that diuresis, per se, is not the cause of the decrease in AQP2 levels. Following release of the obstruction, there is a marked polyuria, which initially is primarily osmotic. However, the polyuria persists for several days after the plasma biochemistry has normalised associated with an increase in solute-free water clearance together with a persistent reduction in AQP2 expression until at 15 days after release obstruction (44±10% of control levels). In paralle,l urinary concentrating capacity was impaired, evidenced as an inability to increase urine osmolality in response to thirst (1773±218 vs. 2880± 81 mosm/kg) consistent with impairment of collecting duct water reabsorption.
In order to examine whether the reduction in AQP2 expression in BUO was caused by local effects or systemic changes in the animal, experiments were performed with UUO for 24 hours. Similar to conditions with BUO AQP2 levels were reduced to 23±7% of control levels. Also AQP2 mRNA levels were reduced in obstructed kidneys. This downregulation of AQP2 persisted 24 hours after release. Interestingly, AQP2 levels were also reduced in the contralateral non-obstructed kidney (75±7%), suggesting a role of AQP2 in the compensatory increase in urine output. Importantly, and consistent with impairment of collecting duct water reabsorption, solute free water clearances were changed in parallel, supporting a role of AQP2 downregulation in postobstructive polyuria. Immunocytochemistry confirmed the marked decrease in AQP2 expression. Evidence for the presence of a vasopressin-independent regulation of AQP2 has been provided, and recent data where we used Brattleboro rats with UUO revealed a similar downregulation as previously found in normal UUO rats (39±10% of controls) indicating that vasopressin-independent pathways are important in this downregulation. In addition we have found that both AQP1, AQP2 and AQP3 are downregulated up to 30 days after release of obstruction suggesting that both the proximal tubule and the collecting duct are critically involved in the concentrating defect associated with postobstructive polyuria.
Each kidney has a ureter, a fibromuscular tube 16 to 18 inches long, that conveys urine from the kidney to the bladder. Sometimes one or both of the ureters becomes obstructed (a unilateral ureteral obstruction (UUO) or bilateral ureteral obstruction (BUO), causing urinary problems. When either the UUO or BUO is cleared, the patient often experiences a period of polyuria (the chronic passage of large volumes of urine). This period of polyuria indicates a reduction in the patient's ability to concentrate urine, a reduction that is not correctable by treatment with vasopressin (VP).
Frøkiær, et al., examined whether the urinary concentrating defect that occurs after the release of either UUO or BUO is related to changes in the number of aquaporin-2s (AQP2s) expressed in the principal cells of the kidney collecting ducts. Experimenting on rats, the researchers found that after both the rats' ureters were obstructed for 24 hours, the number of AQP2s expressed in their collecting duct principal cells was markedly reduced. After the obstruction was released, the rats experienced polyuria and their numbers of AQP2 did not return to normal for 15 days after the obstruction was released.
To determine whether the reduction in AQP2 numbers in BUO rats was caused by local effects or systemic changes in the rats, the researchers worked with a group of rats with UUO. After 24 hours of obstruction, the number of AQP2s in the obstructed kidney were markedly reduced and stayed so for 24 hours. Also, the kidney whose ureter was not obstructed also had a reduction in the number of AQP2s, though not as marked as the obstructed kidney. Thus, the researchers found an association of downregulation of AQP2 numbers and postobstruction polyuria and showed that there are other ways to regulate AQP2 than by VP.
Working with rats that are congenitally unable to produce VP, the researchers again found a decrease in AQP2s during and after ureteral obstruction. This proves that VP-independent molecular pathways are important in the AQP2 downregulation. In conclusion, the researchers have shown that AQP2 may play a critical role for the concentrating defect associated with postobstructive polyuria.