Glomerular and tubular induction of the transcription factor c-Jun in human renal disease

M.H. de Borst*, J. Prakash, W.B.W.H. Melenhorst, M.C. van den Heuvel, R.J. Kok, G. Navis, H. van Goor

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

The transcription factor c-Jun regulates the expression of genes involved in proliferation and inflammation in many cell types but its role in human renal disease is largely unclear. In the current study we investigated whether c-Jun activation is associated with human renal disease and if c-Jun activation regulates pro-inflammatory and pro-fibrotic genes in renal cells. Activation of c-Jun was quantified by scoring renal expression of phosphorylated c-Jun (pc-Jun) in control human renal tissue and in biopsies from patients with various renal diseases (diabetic nephropathy, focal glomerulosclerosis, hypertension, IgA nephropathy, membranous glomerulopathy, minimal change disease, membranoproliferative glomerulonephritis, systemic lupus erythematosus, acute rejection, and Wegener's granulomatosis); this was correlated with parameters of renal damage. Furthermore, we studied the functional role of c-Jun activation in human tubular epithelial cells (HK-2) stimulated with TGF-β. Activated c-Jun was present in nuclei of glomerular and tubular cells in all human renal diseases, but only sporadically in controls. Across the diseases, the extent of pc-Jun expression correlated with the degree of focal glomerulosclerosis, interstitial fibrosis, cell proliferation, kidney injury molecule-1 (Kim-1) expression, macrophage accumulation, and impairment of renal function. In HK-2 cells, TGF-β induced c-Jun activation after 1 h (+40%, p < 0.001) and 24 h (+160%, p < 0.001). The specific c-Jun N-terminal kinase (JNK) inhibitor SP600125 abolished c-Jun phosphorylation at all time points and blunted TGF-β- or BSA-induced procollagen-1α 1 and MCP-1 gene expression in HK-2 cells. We conclude that in human renal disease, the transcription factor c-Jun is activated in glomerular and tubular cells. Activation of c-Jun may be involved in the regulation of inflammation and/or fibrosis in human renal disease.

Original languageEnglish
Pages (from-to)219-228
Number of pages10
JournalJournal of pathology
Volume213
Issue number2
DOIs
Publication statusPublished - 1 Oct 2007
Externally publishedYes

Keywords

  • Activator protein-1 (AP-1)
  • Biopsy
  • c-Jun
  • c-Jun N-terminal kinase (JNK)
  • Human renal disease
  • Kidney

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