Objective: Renal fibrosis was induced by unilateral ureteral obstruction (UUO) in the wild type and γGT(+); Sirt6fl/fl mice for 7 days. Histologic examination and Western blot analysis for α-SMA, type I collagen were performed. We also evaluated cell adhesion molecule expression after ureteral obstruction.   Methods: We generated mice with conditional knockout of Sirt6 in renal proximal tubule epithelial cells by combining floxed Sirt6 and Cre recombinase under the control of gamma-glutamyl transferase promoter. This proximal tubule specific Sirt6 knockout mouse shows decrease expression of Sirt6 after immunofluorescence staining after 1 week of ureteral obstruction. Renal tubular injury and fibrosis were increased after ureteral obstruction in γGT(+); Sirt6fl/fl mice compared to wild type. The number of α-SMA positive fibroblasts and F4/80 positive macrophages were significantly increased after ureteral obstruction in γGT(+); Sirt6fl/fl mice. In Western blot analysis, α-SMA, type I collagen, and intercellular adhesion molecule (ICAM)-1 expression was increased after ureteral obstruction in γGT(+); Sirt6fl/fl mice.   Results: These results suggest that proximal tubule specific Sirt6 has protective roles in UUO-induced renal fibrosis.   Conclusions: Objective: Renal fibrosis is a common feature of all progressive chronic kidney diseases. Sirt6 is a chromatin regulatory protein in the Sirtuin family of NAD+ -dependent enzymes. Sirt6 has diverse roles in aging, metabolism, and disease. This study investigates the effect of proximal tubule specific Sirt6 knock-down on unilateral ureteral obstruction-induced renal tubulointerstitial fibrosis.   Methods: Renal fibrosis was induced by unilateral ureteral obstruction (UUO) in the wild type and γGT(+); Sirt6fl/fl mice for 7 days. Histologic examination and Western blot analysis for α-SMA, type I collagen were performed. We also evaluated cell adhesion molecule expression after ureteral obstruction.   Results: We generated mice with conditional knockout of Sirt6 in renal proximal tubule epithelial cells by combining floxed Sirt6 and Cre recombinase under the control of gamma-glutamyl transferase promoter. This proximal tubule specific Sirt6 knockout mouse shows decrease expression of Sirt6 after immunofluorescence staining after 1 week of ureteral obstruction. Renal tubular injury and fibrosis were increased after ureteral obstruction in γGT(+); Sirt6fl/fl mice compared to wild type. The number of α-SMA positive fibroblasts and F4/80 positive macrophages were significantly increased after ureteral obstruction in γGT(+); Sirt6fl/fl mice. In Western blot analysis, α-SMA, type I collagen, and intercellular adhesion molecule (ICAM)-1 expression was increased after ureteral obstruction in γGT(+); Sirt6fl/fl mice.   Conclusions: These results suggest that proximal tubule specific Sirt6 has protective roles in UUO-induced renal fibrosis.