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Am J Physiol Renal Physiol 277: F219-F226, 1999;
0363-6127/99 $5.00
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Vol. 277, Issue 2, F219-F226, August 1999

Cyclooxygenase inhibitors increase Na-K-2Cl cotransporter abundance in thick ascending limb of Henle's loop

Patricia Fernández-Llama1, Carolyn A. Ecelbarger1, Joseph A. Ware2, Peter Andrews3, Alanna J. Lee1, Rachel Turner1, Søren Nielsen4, and Mark A. Knepper1

1 Laboratory of Kidney and Electrolyte Metabolism and 2 Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, Bethesda, Maryland 20892; 3 Department of Cell Biology, Georgetown University School of Medicine, Washington, District of Columbia 20007; and 4 Department of Cell Biology, Institute of Anatomy, University of Aarhus, DK-8000 Aarhus, Denmark

Cyclooxygenase inhibitors, such as indomethacin and diclofenac, have well-described effects to enhance renal water reabsorption and urinary concentrating ability. Concentrating ability is regulated in part at the level of the thick ascending limb of Henle's loop, where active NaCl absorption drives the countercurrent multiplication mechanism. We used semiquantitative immunoblotting to test the effects of indomethacin and diclofenac, given over a 48-h period, on the expression levels of the ion transporters responsible for active NaCl transport in the thick ascending limb. Both agents strongly increased the expression level of the apical Na-K-2Cl cotransporter in both outer medulla and cortex. Neither agent significantly altered outer medullary expression levels of other thick ascending limb proteins, namely, the type 3 Na/H exchanger (NHE-3), Tamm-Horsfall protein, or alpha 1- or beta 1-subunits of the Na-K-ATPase. Administration of the EP3-selective PGE2 analog, misoprostol, to indomethacin-treated rats reversed the stimulatory effect of indomethacin on Na-K-2Cl cotransporter expression. We conclude that cyclooxygenase inhibitors enhance urinary concentrating ability in part through effects to increase Na-K-2Cl cotransporter expression in the thick ascending limb of Henle's loop. This action is most likely due to elimination of an EP3-receptor-mediated tonic inhibitory effect of PGE2 on cAMP production.

urinary concentration mechanism; prostaglandins; indomethacin; diclofenac


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