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Am J Physiol Renal Physiol 292: F837-F844, 2007. First published September 12, 2006; doi:10.1152/ajprenal.00254.2006
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Renal upregulation of HO-1 reduces albumin-driven MCP-1 production: implications for chronic kidney disease

¹Division of Nephrology and Hypertension, ²Department of Laboratory Medicine and Pathology, ³Department of Pediatrics and Adolescent Medicine, ⁴Department of Immunology, ⁵Division of Infectious Diseases, ⁶Program in Translational Immunovirology and Biodefense, Mayo Clinic College of Medicine, Rochester, Minnesota; and ⁷Department of Molecular Genetics, Alton Ochsner Medical Foundation, New Orleans, Louisiana

Submitted 5 July 2006 ; accepted in final form 5 September 2006

Proteinuria contributes to chronic kidney disease by stimulating renal tubular epithelial cells to produce cytokines such as monocyte chemoattractant protein-1 (MCP-1). The present study determined whether cellular overexpression of heme oxygenase-1 (HO-1) can influence albumin-stimulated MCP-1 production. In response to bovine serum albumin, NRK-52E cells constitutively overexpressing HO-1 (HO-1 OE cells) exhibit less induction of MCP-1 mRNA and less production of MCP-1 protein compared with similarly treated, control NRK-52E cells (CON cells). In wild-type NRK-52E cells, and under these conditions, we demonstrate that the induction of MCP-1 is critically dependent on intact NF-B binding sites in the MCP-1 promoter. In response to albumin, CON cells exhibit activation of NF-B, and this is reduced in HO-1 OE cells. Albumin also activates ERK1/2 and increases ERK activity, both of which are exaggerated in HO-1 OE cells. Studies with an inhibitor of MAPK/ERK kinase (U0126) demonstrate that the inhibitory effects of U0126 on MCP-1 production are attenuated in HO-1 OE cells. We conclude that HO-1 overexpression in the proximal tubule reduces MCP-1 production in response to albumin, and this occurs, at least in part, by inhibiting an ERK-dependent, NF-B-dependent pathway at a site that is distal to the activation of ERK. These findings suggest that the induction of HO-1 in the proximal tubule, as occurs in chronic kidney disease, may be a countervailing response that reduces albumin-stimulated production of cytokines such as MCP-1.

proteinuria; extracellular signal-regulated kinase 1/2; tubulointerstitial disease; cytoprotection

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