Prevention of diabetic nephropathy in rats through enhanced renal antioxidative capacity by inhibition of the proteasome

Aims: Oxidative stress may play an important role in the pathogenesis of diabetic nephropathy (ON). Recent studies have shown that the ubiquitin-proteasome pathway (UPP) and oxidative stress have interaction. We aimed to investigate whether inhibiting the proteasome has a preventive effect on ON through suppression of renal oxidative stress. Main methods: Male Sprague-Dawley rats were randomly divided into three groups: a normal control (NC) group, a streptozotocin-induced ON model group, and a DN plus MG132 (10 mu g/kg) treatment group. Key findings: Increased 24-h urinary protein excretion rate (UPER) and renal pathological changes were all improved after MG132 administration. Furthermore, enhanced renal 26S proteasome activity and concentration in DN rats were effectively reduced after MG132 administration. Increased p47phox and nitrotyrosine (NT) expressions in kidneys of DN rats were decreased after MG132 treatment. Renal mRNA and protein expressions of NF-E2 related factor 2 (Nrf2) were up-regulated by MG132 in comparison to ON alone. Decreased renal mRNA expression of superoxide dismutase 1 (SOD1), catalase (CAT) and glutathione peroxidase (GPx) in DN rats was heightened after MG132 intervention. Depressed activities of renal SOD. CAT and GPx in ON rats were also improved by MG132 treatment. Increased renal nuclear factor kappa B (NF-kappa B) activity was inhibited after MG132 administration in ON rats at the end of 12 weeks. Significance: Our present data suggest that inhibition of the proteasome by low-dose MG132 has a preventive effect on ON development and progression in rats through the up-regulation of antioxidant genes. (C) 2011 Elsevier Inc. All rights reserved.