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1The Water and Salt Research Center, 2Institute of Clinical Medicine, 5Institute of Anatomy, University of Aarhus, 7Department of Clinical Physiology, 3The MR Research Centre, and 6Department of Urology, Aarhus University Hospital-Skejby, Aarhus, Denmark; and 4Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
Submitted 27 June 2006 ; accepted in final form 2 October 2006
Angiotensin II (ANG II) plays an important role in the development of obstructive nephropathy. Here, we examined the effects of the ANG II receptor type 1 (AT1R) blockade using candesartan on long-term renal molecular and functional changes in response to partial unilateral ureteral obstruction (PUUO). Newborn rats were subjected to severe PUUO or sham operation (Sham) within the first 48 h of life. Candesartan was provided in the drinking water (10 mg·kg–1·day–1) from day 21 of life until 10 wk of age. Renal blood flow (RBF) was evaluated by MRI, glomerular filtration rate (GFR) was measured using the renal clearance of 51Cr-EDTA, and the renal expression of Na-K-ATPase and the collecting duct water channel aquaporin-2 (AQP2) was examined by immunoblotting and immunocytochemistry. At 10 wk of age, PUUO significantly reduced RBF (0.8 ± 0.1 vs. 1.6 ± 0.1 ml·min–1·100 g body wt–1; P < 0.05) and GFR (37 ± 16 vs. 448 ± 111 µl·min–1·100 g body wt–1; P < 0.05) compared with Sham. Candesartan prevented the RBF reduction (PUUO+CAN: 1.6 ± 0.2 vs. PUUO: 0.8 ± 0.1 ml·min–1·100 g body wt–1; P < 0.05) and attenuated the GFR reduction (PUUO+CAN: 265 ± 68 vs. PUUO: 37 ± 16 µl·min–1·100 g body wt–1; P < 0.05). PUUO was also associated with a significant downregulation in the expression of Na-K-ATPase (75 ± 12 vs. 100 ± 5%, P < 0.05) and AQP2 (52 ± 15 vs. 100 ± 4%, P < 0.05), which were also prevented by candesartan (Na-K-ATPase: 103 ± 8 vs. 100 ± 5% and AQP2: 74 ± 13 vs. 100 ± 4%). These findings were confirmed by immunocytochemistry. Consistent with this, candesartan treatment partly prevented the reduction in solute free water reabsorption and attenuated fractional sodium excretion in rats with PUUO. In conclusion, candesartan prevents or attenuates the reduction in RBF, GFR and dysregulation of AQP2 and Na-K-ATPase in response to congenital PUUO in rats, suggesting that AT1R blockade may protect the neonatally obstructed kidney against development of obstructive nephropathy.
congenital ureteral obstruction; newborn rat; aquaporin water channels; sodium transporter; AT1 receptor blockage
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