c-Jun NH2-terminal kinase is crucially involved in renal tubulo-interstitial inflammation

Martin H. De Borst, Jai Prakash*, Maria Sandovici, Pieter A. Klok, Inge Hamming, Robbert Jan Kok, Gerjan Navis, Harry Van Goor

*Corresponding author for this work

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    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) path-way 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-pyrazoloan-throne (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.

    Original languageEnglish
    Pages (from-to)896-905
    Number of pages10
    JournalJournal of Pharmacology and Experimental Therapeutics
    Volume331
    Issue number3
    DOIs
    Publication statusPublished - 1 Dec 2009

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  • Cite this

    De Borst, M. H., Prakash, J., Sandovici, M., Klok, P. A., Hamming, I., Kok, R. J., ... Van Goor, H. (2009). c-Jun NH2-terminal kinase is crucially involved in renal tubulo-interstitial inflammation. Journal of Pharmacology and Experimental Therapeutics, 331(3), 896-905. https://doi.org/10.1124/jpet.109.154179