Description
Fibrosis results from the imbalance of collagen homeostasis, including collagen fiber organization and collagen degradation. Discoidin domain receptor 1 (DDR1) is a collagen receptors that is upregulated in unilateral ureteral obstruction (UUO)-induced renal fibrosis. We found that TGF-β1, a pro-fibrotic cytokine, induced the upregulation of DDR1 and myofiborblast activation in NRK49F cells. Although knockdown of DDR1 did not reduce TGF-β1-induced myofibroblast activation, it markedly enhanced podosome formation, a component for ECM degradation, through the inhibition of integrin β1 activation. Interestingly, softening the matrix stiffness decreased DDR1 expression, which negatively correlated with podosome formation. Finally, the functional assay for collagen degradation and collagen alignment revealed strong matrix degradation ability and poor collagen aggregation in DDR1-siliencing cells. In summary, we demonstrated that there is a mutually exclusive effect between stress fiber and podosome formation, and DDR1 plays a crucial role in promoting stress fiber formation and inhibiting podosome formation through the integrin β1 activation triggered by mechanical stimuli. The findings from this study illustrate that mechanical stimuli regulate collagen receptors to modulate collagen homeostasis, which provides evidence to further understand fibrosis process.
