Heme: A novel inducer of MCP-1 through HO-dependent and HO-independent mechanisms

Sharan K.R. Kanakiriya, Anthony J. Croatt, Jill J. Haggard, Julie R. Ingelfinger, Shiow Shih Tang, Jawed Alam, Karl A. Nath

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

This study examined the effect of hemin on the expression of heme oxygenase-1 (HO-1) and monocyte chemoattractant protein-1 (MCP-1) in immortalized rat proximal tubular epithelial cells (IRPTCs). Hemin elicited a dose- and time-dependent induction of HO-1 and MCP-1 mRNA. HO activity contributed to MCP-1 mRNA expression at early time points (4-6 h) because inhibition of HO activity by zinc protoporphyrin (ZnPP) prevented hemin-induced expression of MCP-1 mRNA. Catalytically active intracellular iron was markedly increased in hemin-treated IRPTCs and contributed to the induction of HO-1 and MCP-1 mRNA because an iron chelator blocked hemin-induced upregulation of both genes, whereas a cell-permeant form of iron directly induced these genes. N-acetylcysteine completely blocked hemin-induced expression of HO-1 and MCP-1 mRNA, thereby providing added evidence for redox regulation of expression of these genes. The redox-sensitive transcription factor NF-κB was recruited in hemin-induced upregulation of MCP-1 because two different compounds that abrogate the activation of NF-κB (TPCK and BAY 11-7082) completely blocked hemin-induced upregulation of MCP-1 mRNA. In contrast to this HO-mediated induction of MCP-1 through redox-sensitive, iron-dependent, and NF-κB-involved pathways observed after 4-6 h, hemin also elicited a delayed induction of MCP-1 at 18 h through HO-independent pathways. We conclude that hemin is a potent inducer of MCP-1 in IRPTCs: HO-dependent, hemedegrading pathways lead to an early, robust, and selfremitting induction of MCP-1, whereas HO-independent mechanisms lead to a delayed expression of MCP-1.

Original languageEnglish (US)
Pages (from-to)F546-F554
JournalAmerican Journal of Physiology - Renal Physiology
Volume284
Issue number3 53-3
DOIs
StatePublished - Mar 1 2003

Keywords

  • Heme oxygenase
  • Iron
  • Monocyte chemoattractant protein-1
  • Oxidant stress

ASJC Scopus subject areas

  • Physiology
  • Urology

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