2004 Global Researcher Conference Proceeding
April 09 - 11, 2004
| Conference: | 2004 Global Researcher Conference |
|---|---|
| Title: | Candesartan treatment prevents dysregulation of AQP2, BSC-1 and NaPi2 in ureteral obstruction-induced NDI |
| Authors: | Jensen, Anja; Li, Chunling; Frische, PhD, Sebastian; Knepper, Mark; Nielsen, Soren; Frokiaer, Jorgen |
| Institutions: | University of Aarhus, National Institutes of Health, The Water and Salt Research Center, University of Aarhus |
Urinary tract obstruction is a common manifestation, which may cause obstructive nephropathy characterized by unique reductions in renal function including development of nephrogenic diabetes insipidus (NDI). We have previously shown that renal aquaporins and key sodium transporters are long-term downregulated in response to bilateral ureter obstruction in parallel with onset of polyuria and impaired urinary concentrating capacity. Obstructive nephropathy is a complex disease and the renin angiotensin system has been demonstrated to play an important pathophysiological role.
In this series of studies we therefore examined the effect of the angiotensin II Type 1 receptor antagonist, candesartan, on renal expression of aquaporins and sodium transporters in response to bilateral ureteral obstruction (BUO), and after release of BUO (BUO-R) for 3 days. Consistent with previous observations BUO was associated with a marked reduction in the abundance of AQP1, AQP2 and AQP3. Release of BUO was associated with a dramatic polyuria and reduced urine osmolality (559 ± 38 vs. 2262 ± 232 mOsmol/kgH2O in controls, p‹0.05). Consistent with this AQP1, 2 and 3 were persistently downregulated (AQP1: 24 ± 5% vs. 100 ± 10% in controls; AQP2: 13 ± 5 vs. 100 ± 1%; AQP3: 10 ± 5% vs. 100 ± 1%). Moreover, the protein abundance of the Na+ transporters type 2 Na-phosphate cotransporter (NaPi-2) and the type 1 bumetanide sensitive Na+-K+-2Cl- cotransporter (BSC-1 or NKCC2) were markedly reduced by BUO consistent with marked natriuresis. Candesartan treatment for 3 days partially prevented the reduction in AQP2 (66 ± 21%, n=7 vs. 13 ± 2%, n=7; p‹0.05), NaPi-2 (84 ± 6%, n=7 vs. 57 ± 10%, n=7; p‹0.05) and BSC-1 abundance (89 ± 12%, n=7 vs. 46% ± 11 n=7; p‹0.05). These changes in the expression of channels and transporters were paralleled by an increase in renal sodium reabsorption (433 ± 62, n=7 vs. 233 ± 45 µmol/min/kg, n=7; p‹0.05), and reduction in urine output (58 ± 4, n=7 vs. 97 ± 5 µl/min/kg, n=7; p‹0.01) indicating a functional association between these changes. The changes in protein abundance demonstrated by semi-quantitative immunoblotting were confirmed by immunocytochemistry.
In conclusion, blockade of the angiotensin II receptor Type 1 markedly prevents downregulation of AQP2, BSC-1 and NaPi2 and concomitantly attenuates renal water and sodium loss in rats with urinary tract obstruction-induced NDI.
The ureter is a tube that runs from the kidney to the bladder. There is one ureter from each kidney. When both ureters are blocked, the number of AQP2 waterchannels within the kidney as well as the sodium transporters NaPi2 and BSC-1 in the kidney is reduced. NDI may then occur as a result of this.
Several scientists have demonstrated that the renin-angiotensin system – a family of hormones formed by the catalytic action of renin – plays a essential role in kidney diseases that result from both ureters being blocked. Frokiaer, et al., investigated the effect of candesartan – an agent that inhibits the function of the renin angiotensin by blocking the active receptor– on the number of AQP2 and key sodium transporters present in the kidneys. A rat model was used where both ureters are obstructed (BUO) for 24 hours and immediately after the ureters have been released from obstruction (BUO-R). BUO resulted in a significant reduction of AQP1, AQP2 and AQP3 and the key sodium transporters. BUO-R conditions revealed that there is a continued drop in the AQPs and a dramatic increase in the flow of dilute urine.
When the rats were treated with candesartan for three days, the numbers of AQP2, NaPi-2 and BSC-1 did not drop nearly as much. This was accompanied by an increase in the rat kidneys’ ability to reabsorb sodium and urine, thus partially preventing the severity of production of dilute urine.