c-Myc promotes renal fibrosis by inducing integrin αv-mediated transforming growth factor-β signaling

5 years ago

c-Myc promotes renal fibrosis by inducing integrin αv-mediated transforming growth factor-β signaling

Fibrogenesis involves the activation of renal fibroblasts upon kidney injury. However, the mechanisms underlying renal fibroblast activation are poorly characterized. c-Myc is a predominant oncogene encoding a pleiotropic transcription factor that participates in the regulation of various genes, including genes vital for regulating the cell cycle, cell proliferation, and apoptosis. Here we tested whether renal fibrosis in unilateral ureteral obstruction and folic acid–induced renal fibrosis mouse models are associated with the overexpression of c-Myc. Transforming growth factor-β (TGF-β) has been identified as a key mediator of renal fibrosis, and it is secreted in an inactive form as a complex with latency-associated peptide and latent TGF-β–binding proteins. Five αv-containing integrins with different β -subunits can activate TGF-β, and consistent with this we found that c-Myc bound directly to the promoter of integrin αv in renal fibroblasts activating its transcription. This, in turn, induced activation of TGF-β signaling. Pharmacological blockade of c-Myc attenuated renal fibrosis in vivo in the ureteral obstruction and folic acid–treated mouse models and inhibited the proliferation and activation of renal fibroblasts in vitro. Thus, c-Myc overexpression stimulated proliferation and activation of renal fibroblasts by inducing integrin αv -mediated TGF-β signaling. Hence, targeting c-Myc may have clinical utility in the treatment of renal fibrosis.

Publisher URL: www.sciencedirect.com/science

DOI: S0085253817301783