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1 The Water and Salt Research Institute, University of Aarhus, Aarhus, Denmark; Department of Biochemistry and Cell Biology, Kyungpook National University School of Medicine, Taegu, Korea, Republic of
2 The Water and Salt Research Institute, University of Aarhus, Aarhus, Denmark; Institute of Anatomy, University of Aarhus, Aarhus, Denmark
3 Laboratory of Kidney and Electrolyte Metabolism, NHLBI, NIH, Bethesda, USA
4 The Water and Salt Research Institute, University of Aarhus, Aarhus, Denmark; Clinical Institute, University of Aarhus, Aarhus, Denmark
* To whom correspondence should be addressed. E-mail: sn{at}ana.au.dk.
Vasopressin and angiotensin II (AngII), which are known to play a major role in the 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 hypothesize that vasopressin-induced water reabsorption could be attenuated by AngII AT1 receptor blockade in rats. To address this, three protocols were used: 1) dDAVP-treated rats (20ng/h s.c. for 7d, n=8), 2) dDAVP (20ng/h s.c. for 7d) and candesartan (1mg/kg/day s.c. for 7d) co-treated rats (n=8), and 3) vehicle-infused control rats (n=8). All rats were maintained on NaCl-deficient diet (0.1meq Na+/200g bw/d) during the experiment. dDAVP treatment alone resulted in a significant decrease in urine output (3.1 ± 0.2 ml/d) compared to controls (11.5 ± 2.2 ml/d, P<0.05), whereas the urine output was significantly increased in response to dDAVP and candesartan co-treatment (9.8 ± 1.0ml/d, P<0.05). Consistent with this, rats co-treated with dDAVP and candesartan demonstrated decreased urine osmolality (1,319 ± 172 mOsm/KgH2O), compared to rats treated with dDAVP alone (3,476 ± 182 mOsm/KgH2O, P<0.05). Semiquantitative immunoblotting revealed significantly decreased expression of medullary AQP2 and p-AQP2 (AQP2 phosphorylated in the PKA-phosphorylation consensus site Ser-256) in response to dDAVP and candesaratn co-treatment, compared to dDAVP treatment alone. In addition, cortical and medullary AQP1 was also downregulated. The fractional sodium excretion (FENa) and plasma potassium levels were markedly increased and the expression of cortical NHE3, NCC and Na,K-ATPase was significantly decreased in response to dDAVP and candesartan cotreatment. Moreover medullary NKCC2 expression showed a marked gel mobility shift from 160kDa to ~180kDa corresponding to enhanced glycosylation whereas the expression was unchanged. In conclusion, AngII AT1 receptor blockade in dDAVP-treated rats was associated with decreased urine concentration and decreased AQP2 and AQP1 expression. Moreover the FENa was increased in parallel with decreased expression of NHE3, NCC and Na,K-ATPase. These results suggest that AngII AT1 receptor activation plays a significant role in regulation of aquaporin and sodium transporter expression and in modulating urine concentration in vivo.
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