Combination therapy with artemether and enalapril improves type 1 diabetic nephropathy through enhancing antioxidant defense

Previous studies have demonstrated that both artemether and enalapril are effective in treating diabetic nephropathy (DN). However, the effects and underlying mechanisms of their combination in treating DN remain unknown. The experimental DN model was induced by injecting streptozotocin (STZ) into male C57BL/6J mice. Mice were randomly allocated to the Type 1 diabetes control (T1D-ctrl), STZ, STZ + artemether (STZ + Art), STZ + enalapril (STZ + ACEi), or STZ + artemether + enalapril (STZ + Art + ACEi) group. The interventions lasted for 8 weeks. At the end of the experiment, related urine and serum biochemical values, such as urinary albumin excretion (UAE) and fasting blood glucose (FBG), were measured. In addition, blood pressure (BP) and kidney morphologic changes were also evaluated. The expression of oxidative stress related molecules, such as catalase, acetylated SOD2 (k68) and acetylated SOD2 (k122) in the kidney were measured. Results: combination therapy showed more pronounced effects in reducing UAE, FBG, and BP than any single drug. Typical diabetic kidney injuries, such as heavier kidney weight, and glomerular and tubular hypertrophy, were also further alleviated by combination therapy. Combination therapy also up-regulated the expression of catalase and down-regulated the expression of acetylated SOD2 (k68) and acetylated SOD2 (k122). Combination therapy with artemether and enalapril exhibited renoprotective effects in STZ-induced T1D mice superior to a single drug. The mechanism might be associated with their synergistic effects in enhancing antioxidant defense.