leupeptins and Albuminuria

Smad7 is the main negative regulatory protein in the transforming growth factor-β (TGF-β) downstream signaling pathway, which plays an important role in diabetic nephropathy (DN) and may be related to the ubiquitin proteasome pathway (UPP).. We investigated the role of UPP in regulating TGF-β/SMAD signaling and explored the therapeutic effect of the ubiquitin proteasome inhibitor MG132 on DN.. Wistar rats were randomly divided into a diabetes group and a normal control group. Rats in the diabetes group were injected intraperitoneally with streptozotocin. Diabetic rats were then randomly divided into a diabetic nephropathy group (DN group), an MG132 high concentration (MH) group, and an MG132 low concentration (ML) group. After 8 weeks of treatment, 24-hour urinary microalbumin (UAlb), urinary protein/urinary creatinine (Up/Ucr) values, ALT, AST, Bcr, kidney damage, TGF-β, Smad7, fibronectin (FN), and Smurf2 were detected.. The body mass and Smad7 protein expression decreased in DN group, but kidney weight, kidney weight index, UAlb, Up/Ucr, FN and Smurf2 mRNA expression, and TGF-β protein expression increased. However, these changes diminished following treatment with MG132, and a more pronounced effect was evident in MH group compared to ML group.. MG132 alleviates kidney damage by inhibiting Smad7 ubiquitin degradation and TGF-β activation in DN.

Topics: Albuminuria; Animals; Diabetic Nephropathies; Dose-Response Relationship, Drug; Fibronectins; Gene Expression Regulation; Kidney; Leupeptins; Male; Organ Size; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Proteolysis; Random Allocation; Rats; Rats, Wistar; Signal Transduction; Smad7 Protein; Streptozocin; Transforming Growth Factor beta1; Ubiquitin-Protein Ligases; Ubiquitination

The present study tested whether MG132 increases vascular nuclear factor E2-related factor-2 (Nrf2) expression and transcription to provide a therapeutic effect on diabetes-induced pathogenic changes in the aorta. To this end, three-month-old OVE26 diabetic and age-matched control mice were intraperitoneally injected with MG-132, 10  μ g/kg daily for 3 months. OVE26 transgenic type 1 diabetic mice develop hyperglycemia at 2-3 weeks of age and exhibit albuminuria at 3 months of age with mild increases in TNF- α expression and 3-NT accumulation in the aorta. Diabetes-induced significant increases in the wall thickness and structural derangement of aorta were found in OVE26 mice with significant increases in aortic oxidative and nitrosative damage, inflammation, and remodeling at 6 months of diabetes, but not at 3 months of diabetes. However, these pathological changes seen at the 6 months of diabetes were abolished in OVE26 mice treated with MG-132 for 3 months that were also associated with a significant increase in Nrf2 expression in the aorta as well as transcription of downstream genes. These results suggest that chronic treatment with low-dose MG132 can afford an effective therapy for diabetes-induced pathogenic changes in the aorta, which is associated with the increased Nrf2 expression and transcription.

Topics: Albuminuria; Animals; Aorta; Blood Pressure; Diabetes Mellitus, Experimental; Hyperglycemia; Leupeptins; Mice; Mice, Transgenic; NF-E2-Related Factor 2; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha; Tyrosine; Up-Regulation