Abstract
Chronic inflammation is a major outcome determinant in several renal disorders. Induction of monocyte chemoattractant protein (MCP)-1 expression in tubular epithelial cells contributes importantly to the recruitment of inflammatory cells from the circulation toward the damaged tubulo-interstitium. Because the MCP-1 gene contains several c-Jun binding sites, we hypothesized that the c-Jun NH2-terminal kinase (JNK) pathway regulates MCP-1 expression and subsequently tubulo-interstitial inflammation. This was investigated in cultured rat tubular epithelial cells (NRK-52E) and in the rat unilateral ischemia/reperfusion (I/R) model. In NRK-52E cells, the JNK inhibitor anthra(1,9-cd)pyrazol-6(2H)-one-1,9-pyrazoloanthrone (SP600125) reduced interleukin-1β-, transforming growth factor-β-, or bovine serum albumin-induced MCP-1 expression in a potent manner (up to 150-fold). In the rat I/R model, JNK activation was low in controls but induced in tubular cells from 30 min after I/R. The extent of JNK activation correlated with interstitial macrophage accumulation. Treatment with SP600125 (30 mg/kg/day i.p. for 4 days) reduced renal c-Jun activation; MCP-1, osteopontin, and vimentin expression; and interstitial macrophage and T-cell accumulation (all p < 0.05). In human renal disease, we also found induction of JNK activation, which correlated strongly with interstitial macrophage accumulation, tubulointerstitial fibrosis, and renal function loss. In conclusion, these data indicate that the JNK pathway plays an important role in renal inflammation, at least in part through induction of MCP-1 gene expression in tubular epithelial cells.
Footnotes
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This study was supported by Groningen University Institute for Drug Exploration (Groningen, The Netherlands); and the J. K. de Cock Foundation (Groningen, The Netherlands).
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Part of this work was presented at the American Society of Nephrology Renal Week 2006, San Diego, CA.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.154179
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ABBREVIATIONS:
- MCP
- monocyte chemoattractant protein
- MAP
- mitogen-activated protein
- JNK
- c-Jun NH2-terminal kinase
- IL
- interleukin
- I/R
- ischemia/reperfusion
- SP600125
- anthra(1,9-cd)pyrazol-6(2H)-one-1,9-pyrazoloanthrone
- TGF
- transforming growth factor
- BSA
- bovine serum albumin
- DMSO
- dimethyl sulfoxide
- SLE
- systemic lupus erythematosus
- PCR
- polymerase chain reaction
- HRP
- horseradish peroxidase
- AP
- alkaline phosphatase
- PBS
- phosphate-buffered saline
- pc-Jun
- activated (phosphorylated) c-Jun
- pJNK
- activated (phosphorylated) c-Jun NH2-terminal kinase
- MME
- mesangial matrix expansion
- FGS
- focal glomerulosclerosis.
- Received March 31, 2009.
- Accepted August 27, 2009.
- © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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