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摘要
Background/Aims: Defective tissue repair underlies renal tissue degeneration during chronic kidney disease (CKD) progression. Unbalanced presence of TGF-beta opposes effective cell proliferation and differentiation processes, necessary to replace damaged epithelia. TGF-beta 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-beta 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-beta (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-beta 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-beta 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-beta on MDCK cells. Conclusion: Activation of the ALK-5 pathway is not sufficient for the antiproliferative effect of TGF-beta. 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.
- 出版日期2015
