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 NH(2)-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-1beta-, transforming growth factor-beta-, 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.
authors.affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.
authors.forename: Martin H
authors.initials: MH
authors.lastname: de Borst
authors.forename: Jai
authors.initials: J
authors.lastname: Prakash
authors.forename: Maria
authors.initials: M
authors.lastname: Sandovici
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Klok
authors.forename: Inge
authors.initials: I
authors.lastname: Hamming
authors.forename: Robbert Jan
authors.initials: RJ
authors.lastname: Kok
authors.forename: Gerjan
authors.initials: G
authors.lastname: Navis
authors.forename: Harry
authors.initials: H
authors.lastname: van Goor
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D007674:Kidney Diseases / Q000201:enzymology; D007684:Kidney Tubules / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009395:Nephritis, Interstitial / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D055815:Young Adult
chemical_list: D000873:Anthracenes; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D047428:Protein Kinase Inhibitors; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases