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ToxSci Advance Access originally published online on March 21, 2006
Toxicological Sciences 2006 91(2):493-500; doi:10.1093/toxsci/kfj168
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Inducible Nitric Oxide Synthase and Apoptosis in Murine Proximal Tubule Epithelial Cells

Manish M. Tiwari, Kurt J. Messer and Philip R. Mayeux1

Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205

Received December 15, 2005; accepted March 2, 2006

Since inducible nitric oxide synthase (iNOS) and proximal tubule injury are known to be critical determinants of lipopolysaccharide (LPS)-induced renal failure, the role of nitric oxide (NO) in proximal tubule cell apoptosis was examined. An 18-h treatment with a combination of LPS (5 µg/ml) and interferon-{gamma} (IFN-{gamma}, 100 units/ml) synergistically induced iNOS and produced a 20-fold increase in NO generation in the TKPTS murine proximal tubule cell line. NO generation by LPS + IFN-{gamma} was blocked by a specific iNOS blocker, L-N6-(1-iminoethyl)-lysine (L-NIL, 1mM). To assess the role of iNOS-derived NO in proximal tubule cell apoptosis, annexin V– and propidium iodide–labeled cells were analyzed by flow cytometry. Neither the induction of iNOS nor its inhibition produced significant apoptotic cell death in TKPTS cells. Two exogenous NO donors were used to examine the role of NO more directly in proximal tubule apoptosis. Although both sodium nitroprusside (SNP), an iron-containing, nitrosonium cation donor, and S-nitroso-N-acetylpenicillamine (SNAP), a noniron-containing, NO generator, produced a concentration-dependent increase in NO generation, only SNP increased apoptotic cell death in TKPTS cells (5.9 ± 0.7% in control cells vs. 21.6 ± 3.8% in SNP [500µM]-treated cells; n = 4–9; p < 0.01). SNP-mediated tubule cell apoptosis was not dependent on the activation of caspases or p53 but was possibly related to the generation of reactive oxygen species by SNP. Thus, in TKPTS cells induction of iNOS and generation of NO by LPS does not lead to tubular epithelial cell death.

Key Words: iNOS; nitric oxide; apoptosis; proximal tubule; sodium nitroprusside; S-nitroso-N-acetylpenicillamine.


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