Objective: To evaluate the effect of dexmedetomidine on renal fibrosis in a mouse model of renal ischemia-reperfusion (I/R) and the role of serine-threonine kinase (Akt). Methods: Sixty male C57BL/6 mice, aged 8 weeks, weighing 20-25 g, were divided into 5 groups (n=12 each) using a random number table method: sham operation group (S group), renal I/R group (I/R group), renal I/R plus dexmedetomidine group (I/R + D group), renal I/R plus dexmedetomidine plus Akt agonist SC79 group (I/R + D + SC group), and renal I/R plus dexmedetomidine plus normal saline group (I/R+ D+ NS group). Renal I/R injury model was established by clamping the bilateral renal pedicle for 30 min followed by reperfusion.Dexmedetomidine was intraperitoneally injected at 30 min before surgery in I/R+ D, I/R+ D+ SC and I/R+ D+ NS groups.SC79 was intraperitoneally injected as a bolus of 0.04 mg/kg at 1 min of reperfusion, followed by an intraperitoneal injection of the same dose every 24 h until day 7.The serum blood urea nitrogen (BUN) and Scr concentrations were detected at 24 h of reperfusion.Renal tissues were taken, and the damage to the renal tubules was scored.Renal tissues were removed at 14 days of reperfusion to detect the degree of renal fibrosis and expression of collagen 1 (COL1), fibronectin (FN), and α-smooth actin (α-SMA) (by immunofluorescence and Western blot). The expression of phosphorylated Akt (p-Akt) in renal tissues was determined by Western blot at 24 h and 14 day of reperfusion. Results: Compared with group S, the serum BUN and Scr concentrations, renal tubule damage score and degree of renal fibrosis were significantly increased, and the expression of COL1, FN, α-SMA and p-Akt was up-regulated in group I/R (P<0.05). Compared with I/R group, the serum BUN and Scr concentrations, renal tubular damage score and degree of renal fibrosis were significantly decreased, and the expression of COL1, FN, α-SMA and p-Akt was down-regulated in I/R+ D and I/R+ D+ NS groups (P<0.05). Compared with I/R+ D group, the serum BUN and Scr concentrations, renal tubule damage score and degree of renal fibrosis were significantly increased , and the expression of COL1, FN, α-SMA and p-Akt was up-regulated in I/R+ D+ SC group (P<0.05). Conclusion Dexmedetomidine can reduce the degree of renal fibrosis in a mouse model of renal I/R and the mechanism is related to inhibiting activation of Akt.