Mechanisms underlying induction of heme oxygenase-1 by nitric oxide in renal tubular epithelial cells

Mingyu Liang, Anthony J. Croatt, Karl A Nath

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

We examined whether nitric oxide-generating agents influence expression of heme oxygenase-1 (HO-1) in renal proximal tubular epithelial cells, LLC-PK1 cells, and the mechanisms underlying any such effects. In sublytic amounts, the nitric oxide donor sodium nitroprusside induced HO-1 mRNA and protein and HO activity in a dose-dependent and time-dependent fashion; this induction was specific for nitric oxide since the nitric oxide scavenger carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide significantly reduced such induction. The induction of HO activity by sodium nitroprusside, or by another nitric oxide donor, spermine NONOate, was markedly reduced by the iron chelator deferoxamine. Two different thiol-containing agents, N-acetylcysteine and dithiothreitol, blunted such induction of HO by nitric oxide. Downstream products of nitric oxide, such as peroxynitrite or cGMP, were not involved in inducing HO. In higher concentrations (millimolar amounts), sodium nitroprusside induced appreciable cytotoxicity as assessed by lactate dehydrogenase (LDH) release and lipid peroxidation, and both of these effects were markedly reduced by deferoxamine. Inhibition of HO did not affect the cytotoxic effects (measured by LDH release) of sodium nitroprusside. We thus provide the novel description of the induction of HO-1 in renal proximal tubular epithelial cells exposed to nitric oxide donors and provide the first demonstration in kidney-derived cells for the involvement of a redox-based mechanism in such expression. We also demonstrate that, in LLC-PK1 cells exposed to nitric oxide donors, chelatable iron is involved in eliciting the HO-1 response observed at lower concentrations of these donors, and in mediating the cytotoxic effects of these donors when present in higher concentrations.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume279
Issue number4 48-4
StatePublished - 2000

Fingerprint

Heme Oxygenase-1
Nitric Oxide Donors
Nitroprusside
Nitric Oxide
Epithelial Cells
Kidney
LLC-PK1 Cells
Deferoxamine
L-Lactate Dehydrogenase
Iron
Peroxynitrous Acid
Dithiothreitol
Acetylcysteine
Chelating Agents
Sulfhydryl Compounds
Lipid Peroxidation
Oxidation-Reduction
Messenger RNA
Proteins

Keywords

  • Cell injury
  • Deferoxamine
  • Kidney
  • Oxidant stress

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Mechanisms underlying induction of heme oxygenase-1 by nitric oxide in renal tubular epithelial cells. / Liang, Mingyu; Croatt, Anthony J.; Nath, Karl A.

In: American Journal of Physiology - Renal Physiology, Vol. 279, No. 4 48-4, 2000.

Research output: Contribution to journalArticle

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abstract = "We examined whether nitric oxide-generating agents influence expression of heme oxygenase-1 (HO-1) in renal proximal tubular epithelial cells, LLC-PK1 cells, and the mechanisms underlying any such effects. In sublytic amounts, the nitric oxide donor sodium nitroprusside induced HO-1 mRNA and protein and HO activity in a dose-dependent and time-dependent fashion; this induction was specific for nitric oxide since the nitric oxide scavenger carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide significantly reduced such induction. The induction of HO activity by sodium nitroprusside, or by another nitric oxide donor, spermine NONOate, was markedly reduced by the iron chelator deferoxamine. Two different thiol-containing agents, N-acetylcysteine and dithiothreitol, blunted such induction of HO by nitric oxide. Downstream products of nitric oxide, such as peroxynitrite or cGMP, were not involved in inducing HO. In higher concentrations (millimolar amounts), sodium nitroprusside induced appreciable cytotoxicity as assessed by lactate dehydrogenase (LDH) release and lipid peroxidation, and both of these effects were markedly reduced by deferoxamine. Inhibition of HO did not affect the cytotoxic effects (measured by LDH release) of sodium nitroprusside. We thus provide the novel description of the induction of HO-1 in renal proximal tubular epithelial cells exposed to nitric oxide donors and provide the first demonstration in kidney-derived cells for the involvement of a redox-based mechanism in such expression. We also demonstrate that, in LLC-PK1 cells exposed to nitric oxide donors, chelatable iron is involved in eliciting the HO-1 response observed at lower concentrations of these donors, and in mediating the cytotoxic effects of these donors when present in higher concentrations.",
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