Angiotensin II mediates downregulation of aquaporin water channels and key renal sodium transporters in response to urinary tract obstruction.
The renin-angiotensin system is well known to be involved in the pathophysiological changes in renal function after obstruction of the ureter. Previously, we demonstrated that bilateral ureteral obstruction (BUO) is associated with dramatic changes in the expression of both renal sodium transporters and aquaporin water channels (AQPs). We now examined the effects of the AT(1)-receptor antagonist candesartan on the dysregulation of AQPs and key renal sodium transporters in rats subjected to 24-h BUO and followed 2 days after release of BUO (BUO-2R). Consistent with previous observations, BUO-2R resulted in a significantly decreased expression of AQP1, -2, and -3 compared with control rats. Concomitantly, the rats developed polyuria and reduced urine osmolality. Moreover, expression of the type 2 Na-phosphate cotransporter (NaPi-2) and type 1 bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) was markedly reduced, consistent with postobstructive natriuresis. Candesartan treatment from the onset of obstruction attenuated the reduction in GFR (3.1 +/- 0.4 vs. 1.7 +/- 0.3 ml.min(-1).kg(-1)) and partially prevented the reduction in the expression of AQP2 (66 +/- 21 vs. 13 +/- 2%, n = 7; P < 0.05), NaPi-2 (84 +/- 6 vs. 57 +/- 10%, n = 7; P < 0.05), and NKCC2 (89 +/- 12 vs. 46% +/- 11, n = 7; P < 0.05). Consistent with this, candesartan treatment attenuated the increase in urine output (58 +/- 4 vs. 97 +/- 5 microl.min(-1).kg(-1), n = 7; P < 0.01) and the reduction in sodium reabsorption (433 +/- 62 vs. 233 +/- 45 micromol.min(-1).kg(-1), n = 7; P < 0.05) normally found in rats subjected to BUO. Moreover, candesartan treatment attenuated induction of cyclooxygenase 2 (COX-2) expression in the inner medulla, suggesting that COX-2 induction in response to obstruction is regulated by ANG II. In conclusion, candesartan prevents dysregulation of AQP2, sodium transporters, and development of polyuria seen in BUO. This strongly supports the view that candesartan protects kidney function in response to urinary tract obstruction.
Jensen
Anja M
AM
The Water and Salt Research Center, Univ. of Aarhus, Institute of Clinical Medicine/Dept. of Clinical Physiology, Aarhus Univ. Hospital, Brendstrupgaardsvej, DK-8200 Aarhus N., Denmark.
Li
Chunling
C
Praetorius
Helle A
HA
Nørregaard
Rikke
R
Frische
Sebastian
S
Knepper
Mark A
MA
Nielsen
Søren
S
Frøkiaer
Jørgen
J
D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D051398:Aquaporin 1 / Q000378:metabolism; D051399:Aquaporin 2 / Q000378:metabolism; D051400:Aquaporin 3 / Q000378:metabolism; D020346:Aquaporins / Q000378:metabolism*; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D008297:Male; D010710:Phosphates / Q000652:urine; D011141:Polyuria / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000652:urine; D050610:Sodium-Phosphate Cotransporter Proteins, Type II / Q000378:metabolism*; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism*; D064466:Solute Carrier Family 12, Member 1; D013777:Tetrazoles / Q000494:pharmacology; D014517:Ureteral Obstruction / Q000188:drug therapy / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000378:metabolism* / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; C496022:Aqp1 protein, rat; C496025:Aqp2 protein, rat; C496029:Aqp3 protein, rat; D051399:Aquaporin 2; D020346:Aquaporins; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D010710:Phosphates; C578716:Slc12a1 protein, rat; D050610:Sodium-Phosphate Cotransporter Proteins, Type II; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D051398:Aquaporin 1; D051400:Aquaporin 3; D012964:Sodium; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; C081643:candesartan