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

Narayana S. Murali, Allan W. Ackerman, Anthony J. Croatt, Jingfei Cheng, Joseph P. Grande, Shari L. Sutor, Richard J. Bram, Gary D. Bren, Andrew D. Badley, Jawed Alam, Karl A. Nath

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)F837-F844
JournalAmerican Journal of Physiology - Renal Physiology
Volume292
Issue number2
DOIs
StatePublished - Feb 1 2007

Keywords

  • Cytoprotection
  • Extracellular signal-regulated kinase 1/2
  • Proteinuria
  • Tubulointerstitial disease

ASJC Scopus subject areas

  • Physiology
  • Urology

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