ABSTRACT
Objective To observe the dose-response relationship of the GSK-3β inhibitor TDZD-8 in severe acute pancreatitis (SAP) associated kidney injury in rats. In order to identify the most effective class of GSK-3β inhibitor and its effective and reasonable safe dose in SAP associated kidney injury model in rats by comparing three kinds of frequently-used GSK-3β inhibitor TDZD-8, lithium chloride (LiCL), SB216763 in this model. Methods Totally 96 SPF male Wistar rats were randomly(random number) divided into 8 groups (n=12): sham operation group (SO group), severe acute pancreatitis group (SAP group), TDZD-8 pretreatment groups (TD group, marked TD1, TD2, TD3 and TD4 group, respectively) at different dosage (0.25, 0.5, 1.0 and 2.0 mg/kg), LiCL pretreatment groups (L group, 40 mg/kg), and SB216763 pretreatment group (SB group, 1 mg/kg). SAP model was induced by retrograde infusion of 5％ sodium taurocholate into the biliopancreatic duct. Rats in each group were sacrificed at 12 h after operation. Then the mortality, quantity of ascites, serum AMY, Cr, BUN and ALT were recorded, and the pathological changes of pancreatic tissues and kidney tissues were observed. Results Compared with the SO group, the levels of ascites, serum AMY, Cr, BUN, ALT and pancreatic and renal pathologic score in the SAP group were all significantly increased (P<0.05). Compared with the TD1 group, quantity of ascites, serum AMY, Cr, BUN,ALT and pancreatic tissue pathological grading were reduced in different degrees in the TD2, TD3 and TD4 groups with statistically significant difference (P<0.05); ALT values were reduce in different degrees in the TD2 and TD3 groups as compared with the SAP group (P<0.05), while ALT value in the TD4 group was similar to that in the SAP group; compared with the TD2 group, all the indexes in the TD3 group were significant better (P<0.05); Compared with TD3 group (the best group in TD group), the levels of ascites and serum ALT in the L group and SB group had no significant difference (P>0.05), but the levels of AMY, Cr, BUN, ALT, pancreatic and renal pathologic score were significantly reduced in the TD3 group than those in the L and SB groups (P<0.05); compared with the SB group, the values of Cr, BUN, pancreatic and renal pathologic score in the L group were lower (P<0.05). GSK-3βprotein expression in all groups showed no obvious difference (P>0.05), while p-GSK-3β ser9 protein expression in the SAP group was lower than that in the SO group (P<0.05), and p-GSK-3β ser9 protein expression in the TD3, L and SB groups were stronger than that in the SAP group. Among them, p-GSK-3βser9 protein expression was highest in the TD3 group, followed by the L group, finally the SB group, and the differences were statistically significant (P<0.05). Conclusions Among the three different GSK-3βinhibitors, TDZD-8 is the most effective GSK-3β inhibitor for SAP associated with kidney injury in rats. The GSK-3β inhibitor TDZD-81 mg/kg administered intravenously is safe, effective and optimal dosage for attenuating the severity of severe acute pancreatitis associated with kidney injury.