PURPOSE: Tubulointerstitial fibrosis is a final common pathway to end-stage chronic kidney diseases, which are characterized by elevated renal angiotensin II (AngII) production. This peptide participates in kidney damage inducing fibrosis and epithelial mesenchymal transition (EMT). Our aim was to describe potential therapeutic targets in AngII-induced EMT, investigating the blockade of different intracellular pathways. METHODS: Studies were done in human tubular epithelial cells (HK2 cell line), evaluating changes in phenotype and EMT markers (Western blot and immunofluorescence). RESULTS: Treatment of HK2 cells with AngII for 3 days caused transdifferentiation into myofibroblast-like cells. The blockade of MAPKs cascade, using specific inhibitors of p38 (SB203580), extracellular signal-regulated kinase1/2 (ERK; PD98059) and Jun N-terminal kinase (JNK) (SP600125), diminished AngII-induced EMT. The blockade of RhoA/ROCK pathway, by transfection of a RhoA dominant-negative vector or by ROCK inhibition with Y-27632 or fasudil, inhibited EMT caused by AngII. Connective tissue growth factor (CTGF) is a downstream mediator of AngII-induced EMT. MAPKs and ROCK inhibitors blocked CTGF overexpression induced by AngII. HMG-CoA reductase inhibitors, although blocked AngII-mediated kinases activation, only partially diminished EMT and did not regulate CTGF. CONCLUSIONS: These data suggest a potential therapeutic use of kinase inhibitors in renal fibrosis.
PURPOSE: Tubulointerstitial fibrosis is a final common pathway to end-stage chronic kidney diseases, which are characterized by elevated renal angiotensin II (AngII) production. This peptide participates in kidney damage inducing fibrosis and epithelial mesenchymal transition (EMT). Our aim was to describe potential therapeutic targets in AngII-induced EMT, investigating the blockade of different intracellular pathways. METHODS: Studies were done in human tubular epithelial cells (HK2 cell line), evaluating changes in phenotype and EMT markers (Western blot and immunofluorescence). RESULTS: Treatment of HK2 cells with AngII for 3 days caused transdifferentiation into myofibroblast-like cells. The blockade of MAPKs cascade, using specific inhibitors of p38 (SB203580), extracellular signal-regulated kinase1/2 (ERK; PD98059) and Jun N-terminal kinase (JNK) (SP600125), diminished AngII-induced EMT. The blockade of RhoA/ROCK pathway, by transfection of a RhoA dominant-negative vector or by ROCK inhibition with Y-27632 or fasudil, inhibited EMT caused by AngII. Connective tissue growth factor (CTGF) is a downstream mediator of AngII-induced EMT. MAPKs and ROCK inhibitors blocked CTGF overexpression induced by AngII. HMG-CoA reductase inhibitors, although blocked AngII-mediated kinases activation, only partially diminished EMT and did not regulate CTGF. CONCLUSIONS: These data suggest a potential therapeutic use of kinase inhibitors in renal fibrosis.
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