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Angiotensin II AT₁ receptor blockade decreases vasopressin-induced water reabsorption and AQP2 levels in NaCl-restricted rats

¹The Water and Salt Research Center, ³Institute of Anatomy, and ⁵Institute of Clinical Medicine, University of Aarhus, Aarhus, Denmark; ²Department of Biochemistry and Cell Biology, Kyungpook National University School of Medicine, Taegu, Korea; and ⁴Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland

Submitted 28 April 2004 ; accepted in final form 7 December 2004

Vasopressin and ANG II, which are known to play a major role in renal water and sodium reabsorption, are mainly coupled to the cAMP/PKA and phosphoinositide pathways, respectively. There is evidence for cross talk between these intracellular signaling pathways. We therefore hypothesized that vasopressin-induced water reabsorption could be attenuated by ANG II AT₁ receptor blockade in rats. To address this, three protocols were used: 1) DDAVP treatment (20 ng/h sc for 7 days, n = 8); 2) DDAVP (20 ng/h sc for 7 days) and candesartan (1 mg·kg^–1·day^–1 sc for 7 days) cotreatment (n = 8); and 3) vehicle infusion as the control (n = 8). All rats were maintained on a NaCl-deficient diet (0.1 meq Na⁺·200 g body wt^–1·day^–1) during the experiment. DDAVP treatment alone resulted in a significant decrease in urine output (3.1 ± 0.2 ml/day) compared with controls (11.5 ± 2.2 ml/day, P < 0.05), whereas the urine output was significantly increased in response to DDAVP and candesartan cotreatment (9.8 ± 1.0 ml/day, P < 0.05). Consistent with this, rats cotreated with DDAVP and candesartan demonstrated decreased urine osmolality (1,319 ± 172 mosmol/kgH₂O) compared with rats treated with DDAVP alone (3,476 ± 182 mosmol/kgH₂O, P < 0.05). Semiquantitative immunoblotting revealed significantly decreased expression of medullary aquaporin-2 (AQP2) and AQP2 phosphorylated in the PKA phosphorylation consensus site Ser-256 (p-AQP2) in response to DDAVP and candesartan cotreatment compared with DDAVP treatment alone. In addition, cortical and medullary AQP1 was also downregulated. Fractional sodium excretion (FE_Na) and plasma potassium levels were markedly increased, and the expressions of the cortical type 3 Na⁺/H⁺ exchanger (NHE3), thiazide-sensitive Na-Cl cotransporter (NCC), and Na-K-ATPase were significantly decreased in response to DDAVP and candesartan cotreatment. Moreover, medullary type 1 bumetanide-sensitive Na-K-2Cl cotransporter expression showed a marked gel mobility shift from 160 to 180 kDa corresponding to enhanced glycosylation, whereas expression was unchanged. In conclusion, ANG II AT₁ receptor blockade in DDAVP-treated rats was associated with decreased urine concentration and decreased AQP2 and AQP1 expression. Moreover, FE_Na was increased in parallel with decreased expression of NHE3, NCC, and Na-K-ATPase. These results suggest that ANG II AT₁ receptor activation plays a significant role in regulating aquaporin and sodium transporter expression and modulating urine concentration in vivo.

aquaporin; calcium; cAMP; type 1 bumetanide-sensitive Na-K-2Cl cotransporter; urine concentration

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