Investigation of dose-dependent effects of berberine against renal ischemia/reperfusion injury in experimental diabetic rats

Abstract Background Ischemia–reperfusion injury causes various severe morphological and functional changes in diabetic patients. To date, numerous antidiabetic and antioxidant agents have been used for treatment of the disease-related changes. Objectives We aimed to examine effective therapeutic doses or doses of berberine against renal ischemia/reperfusion injury (IRI) in a streptozotocin (STZ)-induced diabetic rat model by histopathological and biochemical analysis. Methods Thirty male Sprague Dawley rats were treated with STZ injection for the development of diabetes, and divided into the following groups: STZ-induced diabetic group (STZ); IRI-induced diabetic group (STZ + IRI); 50 mg/kg berberine (BRB) treated diabetic group after inducing IRI (STZ + IRI + BRB 1 ); 100 mg/kg BRB treated diabetic group after IRI (STZ + IRI + BRB 2 ); 150 mg/kg BRB treated diabetic group after IRI (STZ + IRI + BRB 3 ). Bilateral renal ischemia model was applied for 45 min, then reperfusion was allowed for 14 days in STZ-induced diabetic rats. Renal injury was detected histopathologically. Blood urea nitrogen (BUN), creatinine and lactate dehydrogenase (LDH) levels were measured in serum using the ELISA method. Total antioxidant status (TAS) and total oxidant status (TOS) of renal tissue was studied by spectrophotometric assay. Oxidative stress index (OSI) was calculated as TOS-to-TAS ratio. Tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP), Na + /K + -ATPase (sodium pump), and Ca 2+ -ATPase (calcium ATPase) enzyme levels were measured in tissues using the ELISA method. Anti-apoptotic Bax and pro-apoptotic Bcl-2 protein levels were detected by Western blot analysis. All data were evaluated statistically. Results The highest histopathological score was detected in the STZ + IRI group compared to the other group. BRB administration at the doses of 100 mg/kg and 150 mg/kg markedly improved renal injury. BUN and creatinine levels significantly increased in the STZ + IRI group compared to the STZ group ( p p p p p p 2+ -ATPase and Na + /K + -ATPase enzyme activities decreased in the STZ + IRI group compared to the STZ group ( p p Conclusion Ischemia with diabetes caused severe histopathological and biochemical damage in renal tissue. The high doses of berberine markedly improved histopathological findings, regulated kidney function via decreasing BUN and creatinine levels, and rearranged intercellular ion concentration via increasing Na + /K + -ATPase and Ca 2+− ATPase levels. Berberine showed anti-oxidant, anti-apoptotic, and anti-inflammatory effects. According to these data, we suggest that berberine at the doses of 100 and 150 mg may be used as a potential therapeutic agent to prevent renal ischemic injury.