TY - JOUR
T1 - Heme
T2 - A novel inducer of MCP-1 through HO-dependent and HO-independent mechanisms
AU - Kanakiriya, Sharan K.R.
AU - Croatt, Anthony J.
AU - Haggard, Jill J.
AU - Ingelfinger, Julie R.
AU - Tang, Shiow Shih
AU - Alam, Jawed
AU - Nath, Karl A.
PY - 2003/3/1
Y1 - 2003/3/1
N2 - 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.
AB - 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.
KW - Heme oxygenase
KW - Iron
KW - Monocyte chemoattractant protein-1
KW - Oxidant stress
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UR - http://www.scopus.com/inward/citedby.url?scp=0037369412&partnerID=8YFLogxK
U2 - 10.1152/ajprenal.00298.2002
DO - 10.1152/ajprenal.00298.2002
M3 - Article
C2 - 12556365
AN - SCOPUS:0037369412
SN - 1931-857X
VL - 284
SP - F546-F554
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 3 53-3
ER -