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

    Research output: Contribution to journalArticleAcademicpeer-review

    45 Citations (Scopus)
    1 Downloads (Pure)

    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

    Fingerprint

    JNK Mitogen-Activated Protein Kinases
    Chemokine CCL2
    Inflammation
    Kidney
    Epithelial Cells
    Macrophages
    Reperfusion
    Ischemia
    Osteopontin
    Transforming Growth Factors
    Vimentin
    Bovine Serum Albumin
    Interleukin-1
    Fibrosis
    Binding Sites
    T-Lymphocytes
    Gene Expression
    Genes
    anthra(1,9-cd)pyrazol-6(2H)-one

    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
    De Borst, Martin H. ; Prakash, Jai ; Sandovici, Maria ; Klok, Pieter A. ; Hamming, Inge ; Kok, Robbert Jan ; Navis, Gerjan ; Van Goor, Harry. / c-Jun NH2-terminal kinase is crucially involved in renal tubulo-interstitial inflammation. In: Journal of Pharmacology and Experimental Therapeutics. 2009 ; Vol. 331, No. 3. pp. 896-905.
    @article{59c16ec7175b40dd9eb481536d0e18b1,
    title = "c-Jun NH2-terminal kinase is crucially involved in renal tubulo-interstitial inflammation",
    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.",
    author = "{De Borst}, {Martin H.} and Jai Prakash and Maria Sandovici and Klok, {Pieter A.} and Inge Hamming and Kok, {Robbert Jan} and Gerjan Navis and {Van Goor}, Harry",
    year = "2009",
    month = "12",
    day = "1",
    doi = "10.1124/jpet.109.154179",
    language = "English",
    volume = "331",
    pages = "896--905",
    journal = "Journal of Pharmacology and Experimental Therapeutics",
    issn = "0022-3565",
    publisher = "American Society for Pharmacology and Experimental Therapeutics",
    number = "3",

    }

    De Borst, MH, Prakash, J, Sandovici, M, Klok, PA, Hamming, I, Kok, RJ, Navis, G & Van Goor, H 2009, 'c-Jun NH2-terminal kinase is crucially involved in renal tubulo-interstitial inflammation' Journal of Pharmacology and Experimental Therapeutics, vol. 331, no. 3, pp. 896-905. https://doi.org/10.1124/jpet.109.154179

    c-Jun NH2-terminal kinase is crucially involved in renal tubulo-interstitial inflammation. / De Borst, Martin H.; Prakash, Jai; Sandovici, Maria; Klok, Pieter A.; Hamming, Inge; Kok, Robbert Jan; Navis, Gerjan; Van Goor, Harry.

    In: Journal of Pharmacology and Experimental Therapeutics, Vol. 331, No. 3, 01.12.2009, p. 896-905.

    Research output: Contribution to journalArticleAcademicpeer-review

    TY - JOUR

    T1 - c-Jun NH2-terminal kinase is crucially involved in renal tubulo-interstitial inflammation

    AU - De Borst, Martin H.

    AU - Prakash, Jai

    AU - Sandovici, Maria

    AU - Klok, Pieter A.

    AU - Hamming, Inge

    AU - Kok, Robbert Jan

    AU - Navis, Gerjan

    AU - Van Goor, Harry

    PY - 2009/12/1

    Y1 - 2009/12/1

    N2 - 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.

    AB - 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.

    UR - http://www.scopus.com/inward/record.url?scp=73349139523&partnerID=8YFLogxK

    U2 - 10.1124/jpet.109.154179

    DO - 10.1124/jpet.109.154179

    M3 - Article

    VL - 331

    SP - 896

    EP - 905

    JO - Journal of Pharmacology and Experimental Therapeutics

    JF - Journal of Pharmacology and Experimental Therapeutics

    SN - 0022-3565

    IS - 3

    ER -