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 Peter Grande, Shari L. Sutor, Richard J Bram, Gary D. Bren, Andrew David Badley, Jawed Alam, Karl A Nath

Research output: Contribution to journalArticle

34 Citations (Scopus)

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)
JournalAmerican Journal of Physiology - Renal Physiology
Volume292
Issue number2
DOIs
StatePublished - Feb 2007

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Heme Oxygenase-1
Chemokine CCL2
Chronic Renal Insufficiency
Albumins
Up-Regulation
Kidney
Cytokines
Mitogen-Activated Protein Kinase Kinases
Bovine Serum Albumin
Proteinuria
Epithelial Cells
Binding Sites
Messenger RNA

Keywords

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

ASJC Scopus subject areas

  • Physiology

Cite this

Renal upregulation of HO-1 reduces albumin-driven MCP-1 production : Implications for chronic kidney disease. / Murali, Narayana S.; Ackerman, Allan W.; Croatt, Anthony J.; Cheng, Jingfei; Grande, Joseph Peter; Sutor, Shari L.; Bram, Richard J; Bren, Gary D.; Badley, Andrew David; Alam, Jawed; Nath, Karl A.

In: American Journal of Physiology - Renal Physiology, Vol. 292, No. 2, 02.2007.

Research output: Contribution to journalArticle

Murali, Narayana S. ; Ackerman, Allan W. ; Croatt, Anthony J. ; Cheng, Jingfei ; Grande, Joseph Peter ; Sutor, Shari L. ; Bram, Richard J ; Bren, Gary D. ; Badley, Andrew David ; Alam, Jawed ; Nath, Karl A. / Renal upregulation of HO-1 reduces albumin-driven MCP-1 production : Implications for chronic kidney disease. In: American Journal of Physiology - Renal Physiology. 2007 ; Vol. 292, No. 2.
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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.",
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AU - Cheng, Jingfei

AU - Grande, Joseph Peter

AU - Sutor, Shari L.

AU - Bram, Richard J

AU - Bren, Gary D.

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AU - Nath, Karl A

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AB - 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.

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