Objectives: Tubulointerstitial inflammation and fibrosis are significant pathologic changes in progressive kidney disease, resulting in end-stage renal disease. These pathologic changes are complicated signaling pathways in the regulation of tissue homeostasis, including kidney injury and repair. Sirtuins are a family of NAD+-dependent class II histone deacetylase. Among them, Sirt6 is predominantly a nuclear protein and deacetylate diverse proteins such as H3K9, H3K56. Sirt6 regulates DNA repair, glucose and lipid metabolism, cellular senescence, and inflammation. In this study, we investigate the protective effect of Sirt6 activator, MDL-800, on UUO-induced renal tubulointerstitial inflammation and fibrosis and their possible mechanisms.  Methods: Renal fibrosis was induced by UUO in the seven-week-old C57BL/6 mice for 7 days. To evaluate the therapeutic effect of MDL-800, we treated MDL-800 (10 mg/kg) via intraperitoneal injection one day after UUO surgery. Histologic examination and Western blot analysis for type I collagen were performed. We also evaluated inflammatory cytokines and cell adhesion molecule expression after ureteral obstruction.  Results: Renal tubular injury and fibrosis were increased after ureteral obstruction. After treatment of MDL-800, renal tubular injury and fibrosis were significantly decreased. The number of F4/80 positive macrophages was significantly decreased after MDL-800 treatment in the UUO kidney. In Western blot analysis, type I collagen expression was decreased after MDL-800 treatment in the UUO kidney. Inflammatory cytokines and extracellular matrix protein mRNA levels were decreased after MDL-800 treated UUO kidney in qRT-PCR study.  Conclusions: These results suggest that Sirt6 activation by MDL-800 decreases UUO-induced renal fibrosis and inflammation. Renal Sirt6 might have an important role in the renal fibrosis process.