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Am J Physiol Cell Physiol 273: C1882-C1888, 1997;
0363-6143/97 $5.00
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Vol. 273, Issue 6, C1882-C1888, December 1997

Urea inhibits inducible nitric oxide synthase in macrophage cell line

Sharma S. Prabhakar1,2, Guillermo A. Zeballos1, Martin Montoya-Zavala3, and Claire Leonard3

1 Renal Section, Veterans Affairs Medical Center, Bronx 10468; 2 Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029; and 3 Department of Molecular Biology, Alteon Inc., Ramsey, New Jersey 07446

Macrophage dysfunction is considered an important contributory factor for increased propensity of infections in uremia. Because nitric oxide (NO) is believed to be an effector molecule of macrophage cytotoxicity, we propose that the dysfunction may be related to impaired NO synthesis. To verify this hypothesis, we evaluated macrophage NO synthesis in the presence of urea, a compound that accumulates in renal failure and is believed by some to be a uremic toxin. Macrophages (RAW 264.7 cells) were incubated with bacterial lipopolysaccharide to induce NO synthesis, whereas the test groups had various concentrations of urea in addition. NO synthesis was measured by assaying the supernatant for nitrites and nitrates by chemiluminescence. We observed that urea consistently produced a dose-dependent reversible inhibition of inducible NO production in macrophages, whereas parathormone, another toxin retained in uremia, had no such inhibitory effects. Further studies revealed that mRNA for inducible NO synthase was not inhibited by urea. We thus conclude that urea inhibits inducible NO synthesis in macrophages by a posttranscriptional mechanism and that this may be important in macrophage dysfunction of uremia.

inducible nitric oxide synthesis; macrophage dysfunction; uremia


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