It has been demonstrated that loss of Smad4 in mesangial cells inhibits TGF-β1-induced ECM deposition (Tsuchida et al., 2003), which is further confirmed by our recent finding that specific deletion of Smad4 from renal tubular epithelial cells attenuates the UUO-induced renal fibrosis by suppressing Smad3 responsive promoter activity and decreasing the binding of Smad3 to the target genes independent of its phosphorylation and nuclear translocation (Meng et al., 2012b). The gene discussed is TGFB1; the disease is renal fibrosis.