Renal upregulation of HO-1 reduces albumin-driven MCP-1 production: implications for chronic kidney disease.
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-kappaB binding sites in the MCP-1 promoter. In response to albumin, CON cells exhibit activation of NF-kappaB, 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-kappaB-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.
Murali
Narayana S
NS
Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Ackerman
Allan W
AW
Croatt
Anthony J
AJ
Cheng
Jingfei
J
Grande
Joseph P
JP
Sutor
Shari L
SL
Bram
Richard J
RJ
Bren
Gary D
GD
Badley
Andrew D
AD
Alam
Jawed
J
Nath
Karl A
KA
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D007668:Kidney / Q000201:enzymology*; D007676:Kidney Failure, Chronic / Q000503:physiopathology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D051381:Rats; D012710:Serum Albumin, Bovine / Q000494:pharmacology*; D015854:Up-Regulation
D002070:Butadienes; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D016328:NF-kappa B; D009570:Nitriles; C113580:U 0126; D012710:Serum Albumin, Bovine; D051547:Heme Oxygenase-1; D048049:Extracellular Signal-Regulated MAP Kinases