Oleanolic acid and N-acetylcysteine ameliorate diabetic nephropathy through reduction of oxidative stress and endoplasmic reticulum stress in a type 2 diabetic rat model

Hyperglycemia-induced endoplasmic reticulum (ER) stress and oxidative stress could be causes of renal fibrosis in diabetes. Oleanolic acid (OA) naturally occurs in fruits and vegetables. It has anti-inflammatory, antihyperlipidemic and antioxidant effects. N-acetylcysteine (NAC) is a precursor of glutathione, which has a strong antioxidant effect in the body. In this study, we investigated the therapeutic effects of OA and NAC in diabetic nephropathy (DN). Otsuka Long-Evans Tokushima Fatty rats were treated with OA (100 mg/kg/day) or NAC (300 mg/kg/day) for 20 weeks by oral gavage. The OA or NAC administration increased blood insulin secretion and superoxide dismutase levels, and decreased triglycerides and urinary albumin/creatinine levels. In the kidney, the damaged renal structure recovered with OA or NAC administration, through an increase in nephrin and endothelial selective adhesion molecules and a decrease in transforming growth factor-beta/p-smad2/3 and ER stress. Reactive oxygen species and ER stress were increased by high glucose and ER stress inducers in cultured mesangial cells, and these levels recovered with OA (5.0 mu M) or NAC (2.5 mM) treatment. The findings in this study suggest that OA and NAC have therapeutic effects for DN through an antioxidant effect and ER stress reduction.