title: Activation of the ALK-5 Pathway is not per se Sufficient for the Antiproliferative Effect of TGF-β1 on Renal Tubule Epithelial Cells.
abstract: OBJECTIVE
  Defective tissue repair underlies renal tissue degeneration during chronic kidney disease (CKD) progression. Unbalanced presence of TGF-β opposes effective cell proliferation and differentiation processes, necessary to replace damaged epithelia. TGF-β also retains arrested cells in a fibrotic phenotype responsible for irreversible scarring. In order to identify prospective molecular targets to prevent the effect of TGF-β during CKD, we studied the signaling pathways responsible for the antiproliferative effect of this cytokine.
  
  
  METHODS
  Tubule epithelial HK2 and MDCK cells were treated with TGF-β (or not as control) to study cell proliferation (by MTT), cell signaling (by Western blot), cell cycle (by flow cytometry) and apoptosis (DNA fragmentation).
  
  
  RESULTS
  TGF-β fully activates the ALK-5 receptor pathway, whereas it has no effect on the ALK-1 and MAPK pathways in both HK2 and MDCK cells. Interestingly, TGF-β exerts an antiproliferative effect only on MDCK cells, through a cytostatic effect in G0/G1. Inhibition of the ALK-5 pathway with SB431542 prevents the cytostatic effect of TGF-β on MDCK cells.
  
  
  CONCLUSIONS
  Activation of the ALK-5 pathway is not sufficient for the antiproliferative effect of TGF-β. The presence of undetermined permissive conditions or absence of undetermined inhibitory conditions seems to be necessary for this effect. The ALK-5 pathway appears to provide targets to modulate fibrosis, but further research is necessary to identify critical circumstances allowing or inhibiting its role at modulating tubule epithelial cell proliferation and tubule regeneration in the context of CKD progression.
authors.forename: Omar
authors.initials: O
authors.lastname: García-Sánchez
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Sancho-Martínez
authors.forename: José Miguel
authors.initials: JM
authors.lastname: López-Novoa
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: López-Hernández
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D053938:DNA Fragmentation / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology; D061985:Madin Darby Canine Kidney Cells; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D004149:Dioxoles; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human