SIRT1, a class III histone deacetylase, is considered a key regulator of cell survival and apoptosis through its interaction with nuclear proteins. In this study, we examined the possibility and role of the interaction between SIRT1 and Smad7, which mediates TGFß-induced apoptosis in renal glomerular mesangial cells. Immunoprecipitation analysis revealed that SIRT1 directly interacts with the N-terminus of Smad7. Furthermore, SIRT1 reversed acetyl-transferase (p300)-mediated acetylation of two lysine residues (K64 and K70) on Smad7. In mesangial cells, Smad7 expression level was reduced by SIRT1-overexpression and increased by SIRT1-knockdown. SIRT1-mediated deacetylation of Smad7 enhanced Smad ubiquitination regulatory factor 1(Smurf1)-mediated ubiquitin proteasome degradation, which contributed to the low expression of Smad7 in SIRT1-overexpressing mesangial cells. Stimulation by TGFß or overexpression of Smad7 induced mesangial cell apoptosis, as assessed by morphological apoptotic changes (nuclear condensation) and biological apoptotic markers (cleavages of caspase3 and poly (ADP-ribose) polymerase (PARP). However, TGFß failed to induce apoptosis in Smad7-knockdown mesangial cells, indicating that Smad7 mainly mediates TGFß-induced apoptosis of mesangial cells. Finally, SIRT1-overexpression attenuated both Smad7- and TGFß-induced mesangial cell apoptosis, whereas SIRT1-knockdown enhanced this apoptosis. We conclude that Smad7 is a new target molecule for SIRT1, and SIRT1 attenuates TGFß-induced mesangial cell apoptosis through acceleration of Smad7 degradation. Our results suggest that up-regulation of SIRT1 deacetylase activity is a potentially useful therapeutic strategy for prevention of TGFß-related kidney disease through its effect on cell survival.