title: Pharmacological modulation of epithelial mesenchymal transition caused by angiotensin II. Role of ROCK and MAPK pathways.
abstract: OBJECTIVE
  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.
authors.affiliation: Cellular Biology in Renal Diseases Laboratory, Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Rodrigues-Díez
authors.forename: Gisselle
authors.initials: G
authors.lastname: Carvajal-González
authors.forename: Elsa
authors.initials: E
authors.lastname: Sánchez-López
authors.forename: Juan
authors.initials: J
authors.lastname: Rodríguez-Vita
authors.forename: Raúl
authors.initials: R
authors.lastname: Rodrigues Díez
authors.forename: Rafael
authors.initials: R
authors.lastname: Selgas
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
authors.forename: Sergio
authors.initials: S
authors.lastname: Mezzano
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000069059:Atorvastatin; D002460:Cell Line; D054338:Cell Transdifferentiation / Q000187:drug effects*; D055513:Connective Tissue Growth Factor; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D005355:Fibrosis; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: C526317:CCN2 protein, human; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor; D000069059:Atorvastatin; D019821:Simvastatin; D054460:rho-Associated Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020742:rhoA GTP-Binding Protein