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Articles in PresS, published online ahead of print July 30, 2002
Am J Physiol Renal Physiol, 10.1152/ajprenal.00040.2002
Submitted on January 29, 2002
Accepted on July 23, 2002
1 The Water and Salt Research Center, University of Aarhus, Aarhus, Denmark; Department of Physiology, Dongguk Univ, Kyungju, Korea, Republic
2 The Water and Salt Research Center, University of Aarhus, Aarhus, Denmark; Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
3 Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
* To whom correspondence should be addressed. E-mail: sn{at}ana.au.dk.
The purpose of this study was to evaluate whether hypercalcemia (HC) is associated with downregulation of renal aquaporins, including AQP1, AQP2, phosphorylated-AQP2, AQP3, and AQP4, and if this is the case to test whether cAMP-phosphodiesterase inhibitor treatment can prevent AQP downregulation and prevent the development of polyuria. Vitamin-D-induced HC in rats was associated with increased urine output and reduced urine osmolality, consistent with previous findings (20). Semiquantitative immunoblotting revealed a significant reduction in the abundance of inner medullary AQP2 (52±6% of control levels), consistent with previous studies, and of AQP2 which is phosphorylated at the PKA phosphorylation consensus site serine 256 (p-AQP2; 36 ± 8%). Moreover, AQP3 abundance was also significantly decreased (45 ± 7% and 61 ± 6% of control levels in inner medulla and whole kidney, respectively). Consistent with this, immunohistochemistry demonstrated reduced AQP3 immunolabeling along the entire collecting duct. AQP4 expression was not reduced. Surprisingly, total kidney AQP1 abundance was also reduced (60 ± 6%). AQP1 expression was reduced in cortex and outer stripe of the outer medulla (48 ± 7%; i.e. in proximal tubules). In contrast, AQP1 levels were not changed in inner stripe of the outer medulla or in inner medulla (i.e. descending thin limbs and vasa recta). Treatment with the cAMP-phosphodiesterase inhibitors rolipram and milrinone in combination (inhibiting PDE-IV and III isoenzymes) at day two and onwards completely prevented the HC-induced downregulation of AQP2 and AQP3 (but not AQP1) and completely prevented the development of polyuria. In conclusion: AQP3, AQP2, and p-AQP2 is downregulated and are likely to play critical roles in the development of polyuria associated with vitamin-D induced HC. Moreover, PDE inhibitor treatment significantly prevented the reduced expression of collecting duct AQPs and prevented the development of polyuria.
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