Mechanisms underlying induction of heme oxygenase-1 by nitric oxide in renal tubular epithelial cells. Am J Physiol Renal Physiol 2000 Oct;279(4):F728-35
Date
09/21/2000Pubmed ID
10997923DOI
10.1152/ajprenal.2000.279.4.F728Scopus ID
2-s2.0-0033711053 (requires institutional sign-in at Scopus site) 45 CitationsAbstract
We examined whether nitric oxide-generating agents influence expression of heme oxygenase-1 (HO-1) in renal proximal tubular epithelial cells, LLC-PK(1) 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-PK(1) 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.
Author List
Liang M, Croatt AJ, Nath KAMESH terms used to index this publication - Major topics in bold
AnimalsChelating Agents
Deferoxamine
Dose-Response Relationship, Drug
Enzyme Induction
Epithelial Cells
Heme Oxygenase (Decyclizing)
Heme Oxygenase-1
Kidney Tubules, Proximal
L-Lactate Dehydrogenase
LLC-PK1 Cells
Lipid Peroxides
Nitric Oxide
Nitric Oxide Donors
Nitrogen Oxides
Nitroprusside
Oxidative Stress
RNA, Messenger
Spermine
Swine
