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ToxSci Advance Access published online on March 21, 2006
Toxicological Sciences, 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
Received January 5, 2006
Accepted March 6, 2006

In Vitro Toxicology

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

Manish M. Tiwari 1, Kurt J. Messer 1, and Philip R. Mayeux 1 *

1 Department of Pharmacology & Toxicology, University of Arkansas for Medical Sciences, 4301 West Markham Street, # 611Little Rock, AR 72205

* To whom correspondence should be addressed.
Philip R. Mayeux, E-mail: prmayeux{at}uams.edu


  Abstract

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 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 non-iron 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 (500 µM)-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.

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