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Nitric oxide stimulates cyclooxygenase-2 in cultured cTAL cells through a p38-dependent pathway

George M. O'Brien Kidney and Urologic Diseases Center and Division of Nephrology, Vanderbilt University School of Medicine and Nashville Veterans Affairs Hospital, Nashville, Tennessee

Submitted 4 August 2005 ; accepted in final form 19 December 2005

To examine the interaction of nitric oxide (NO) and cyclooxygenase (COX-2) and the signaling pathway involved, primary cultured rabbit cortical thick ascending limb (cTAL) were used. In these cells, immunoreactive COX-2 and vasodilatory prostaglandins were increased by a NO donor, S-nitros-N-acetylpenicillamine (SNAP; 2.5 ± 0.3-fold control, n = 6, P < 0.01). SNAP increased expression of phosphorylated p38 (pp38; 2.4 ± 0.3-fold control; n = 5; P < 0.01), which was inhibited by the p38 inhibitor SB-203580 (1.3 ± 0.1-fold control, n = 5, P < 0.01). SB-203580 inhibited SNAP-induced COX-2 expression [1.4 ± 0.2-fold control, n = 6, not significant (NS) vs. control] and levels of PGE₂ significantly. In cTAL cells transfected with a luciferase reporter driven by the wild-type mouse COX-2 promoter, SNAP stimulated luciferase activity, which was reversed by SB-203580 (control vs. SNAP vs. SNAP + SB-203580: 1.4 ± 0.2-, 8.3 ± 1.4-, and 0.4 ± 0.1-fold control, respectively, n = 4, P < 0.01). Electrophoretic mobility shift assay indicated that SNAP stimulated nuclear factor (NF)-B binding activity in cTAL that was also inhibited by the p38 inhibitor. SNAP was not able to stimulate a mutant COX-2 promoter construct that is not activated by NF-B (0.9 ± 0.1, 1.2 ± 0.1, and 1.0 ± 0.2 respectively, n = 4, NS). Low chloride increased COX-2 expression (2.7 ± 0.4-fold control, n = 6, P < 0.01) and pp38 expression (2.8 ± 0.3-fold; n = 5, P < 0.01), which were reversed by the specific NO synthase (NOS) inhibitor 7-nitroindazole. Administration of a low-salt diet increased immunoreactive COX-2 and neuronal NOS (nNOS) in the macula densa and surrounding cTAL of kidneys of wild-type mice but did not significantly elevate COX-2 expression in nNOS^–/– mice. In summary, these studies indicate that, in cTAL, NO can increase COX-2 expression in cTAL and macula densa through p38-dependent signaling pathways via activation of NF-B.

nitric oxide; cylooxygenase-2; nuclear factor-B; p38; transcriptional regulation

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