PURPOSE: To investigate the mechanisms through which dexmedetomidine (DEX) could improve the renal injury in lipopolysaccharide (LPS)-induced acute kidney injury (AKI) and examine how TNF-α or DEX might affect mitochondrial function and renal injury. METHODS: In vivo experiments involved 24 rats randomly allocated to a sham group, an LPS group, and an LPS + DEX group. Serum creatinine, lactate, TNF-α, IL-1β, and IL-6 concentrations, as well as urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels, were measured 0, 3, and 6 h after the start of the experiments. Histopathological examinations were performed to determine the extent of LPS-induced renal injury and recovery by administration of DEX. in vitro, human embryonic kidney 293 cells were treated with or without (control) several concentrations of TNF-α and DEX for 24 h before measurements of the oxygen consumption rate (OCR) under basal conditions and with the addition of oligomycin, carbonylcyanide-p-trifluoromethoxyphenylhydrazone, antimycin A, and rotenone, as well as intracellular reactive oxygen species (ROS) levels. RESULTS: DEX attenuated LPS-induced increases in serum creatinine and IL-6 concentrations. LPS administration caused histological tissue damage in the kidney, but DEX prevented such damage. In vitro, DEX suppressed TNF-α-induced increases in basal OCR and ROS levels and inhibited decreases of ATP production induced by TNF-α. CONCLUSION: DEX has protective effects for cells and tissues of the kidney by inhibiting oxygen consumption and hypoxia or by improving mitochondrial dysfunction via TNF-α in the renal cells. These results might point to DEX being an important new therapeutic target for the treatment of septic AKI.