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1 Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
2 Rochester, Minnesota, United States; Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
3 Dept. of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
4 Division of Nephrology and Hypertension, Dept. of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
5 Dept. of Pediatrics and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
6 Dept. of Pediatrics and Adolescent Medicine, Dept. of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
7 Division of Infectious Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
8 Division of Infectious Diseases, Program in Translational Immunovirology and Biodefense, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
9 Dept. of Molecular Genetics, Alton Ochsner Medical Foundation, New Orleans, Louisiana, United States
* To whom correspondence should be addressed. E-mail: nath.karl{at}mayo.edu.
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 as compared to similarly treated, control NRK-52E cells (CON cells). In wildtype NRK-52E cells, and under these conditions, we demonstrate that the induction of MCP-1 is critically dependent upon 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 MEK (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.
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