Glomerular and tubular induction of the transcription factor c-Jun in human renal disease.
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-beta. 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-beta 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-beta- or BSA-induced procollagen-1alpha 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.
De Borst
M H
MH
Department of Pathology and Laboratory Medicine, University Medical Center Groningen and University of Groningen, The Netherlands. m.h.de.borst@umcg.nl
Prakash
J
J
Melenhorst
W B W H
WB
van den Heuvel
M C
MC
Kok
R J
RJ
Navis
G
G
van Goor
H
H
D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D049109:Cell Proliferation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D005260:Female; D005919:Glomerular Filtration Rate; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D007124:Immunoenzyme Techniques; D007668:Kidney / Q000378:metabolism; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D008562:Membrane Glycoproteins; D016755:Proto-Oncogene Proteins c-jun; D011991:Receptors, Virus; D016212:Transforming Growth Factor beta