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1 Division of Nephrology, Mayo Clinic/Foundation, Rochester, Minnesota 55905; 2 Pediatric Nephrology Unit, Massachusetts General Hospital, Boston, Massachusetts 02114; and 3 Department of Molecular Genetics, Ochsner Clinic/Foundation, New Orleans, Louisiana 70121
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-
B was recruited in hemin-induced
upregulation of MCP-1 because two different compounds that abrogate the
activation of NF-B (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-B-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, heme-degrading pathways lead to an
early, robust, and self-remitting induction of MCP-1, whereas
HO-independent mechanisms lead to a delayed expression of MCP-1.
heme oxygenase; monocyte chemoattractant protein-1; iron; oxidant stress
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