Candesartan prevents long-term impairment of renal function in response to neonatal partial unilateral ureteral obstruction.
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 (51)Cr-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 microl.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 microl.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.
Topcu
Sukru Oguzkan
SO
The Water and Salt Research Ctr., Institute of Clinical Medicine, University of Aarhus, DK-8200 Aarhus, Denmark.
Pedersen
Michael
M
Nørregaard
Rikke
R
Wang
Guixian
G
Knepper
Mark
M
Djurhuus
Jens Christian
JC
Nielsen
Søren
S
Jørgensen
Troels Munch
TM
Frøkiaer
Jørgen
J
D000450:Aldosterone / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D051399:Aquaporin 2 / Q000096:biosynthesis; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D015536:Down-Regulation / Q000187:drug effects; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006869:Hydronephrosis / Q000517:prevention & control; D007676:Kidney Failure, Chronic / Q000517:prevention & control*; D016328:NF-kappa B / Q000096:biosynthesis; D051381:Rats; D012079:Renal Circulation / Q000187:drug effects; D012964:Sodium / Q000652:urine; D000254:Sodium-Potassium-Exchanging ATPase / Q000096:biosynthesis; D013777:Tetrazoles / Q000627:therapeutic use*; D014517:Ureteral Obstruction / Q000151:congenital* / Q000188:drug therapy*
D047228:Angiotensin II Type 1 Receptor Blockers; D051399:Aquaporin 2; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D016328:NF-kappa B; D013777:Tetrazoles; D000450:Aldosterone; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; C081643:candesartan