Background. 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). Aim. 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. Methods. 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. Results. 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. Conclusion. MG132 alleviates kidney damage by inhibiting Smad7 ubiquitin degradation and TGF-β activation in DN. 1. Introduction Diabetic nephropathy (DN) is one of the most prevalent and serious microvascular complications of diabetes mellitus (DM) [1]. Early pathological characteristics are basement membrane thickening, increase in mesangial matrix, and extracellular matrix accumulation, followed by development of glomerulosclerosis and tubulointerstitial fibrosis, eventually leading to irreversible renal damage [2–5]. The exact pathogenesis of diabetic nephropathy has not yet been completely clarified. Smad7 is the main negative regulatory protein and antifibrotic factor in the transforming growth factor β (TGF-β) downstream signaling pathway [6] and can compete with Smad2/3 for binding to the type I TGF-β receptor, blocking Smad2/3 activation. Smad7 can also be transferred to the cell membrane for degradation of Smad2/3 and TGF-β receptor complexes, as well as inhibition of TGF-β signal activation after binding to the Smad ubiquitin regulatory factor 2 (Smurf2). Activation of TGF-β plays an important role in the pathological progress of diabetic nephropathy [7], which involves increased expression of many cytokines, inflammatory cytokines and adhesion molecules, induction
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