Renal upregulation of HO-1 reduces albumin-driven MCP-1 production: implications for chronic kidney disease

• Published in: American journal of physiology. Renal physiology Vol. 292; no. 2; pp. F837 - F844
• Main Authors: Murali, Narayana S., Ackerman, Allan W., Croatt, Anthony J., Cheng, Jingfei, Grande, Joseph P., Sutor, Shari L., Bram, Richard J., Bren, Gary D., Badley, Andrew D., Alam, Jawed, Nath, Karl A.
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.02.2007
• Subjects: Animals; Butadienes - pharmacology; Cell Line; Chemokine CCL2 - biosynthesis; Extracellular Signal-Regulated MAP Kinases - biosynthesis; Heme Oxygenase-1 - biosynthesis; Kidney - enzymology; Kidney diseases; Kidney Failure, Chronic - physiopathology; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - metabolism; Kidneys; Nephrology; NF-kappa B - metabolism; Nitriles - pharmacology; Proteins; Rats; Serum Albumin, Bovine - pharmacology; Up-Regulation
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00254.2006

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-κB binding sites in the MCP-1 promoter. In response to albumin, CON cells exhibit activation of NF-κB, 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-κB-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.