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MG132 ameliorates kidney lesions by inhibiting the degradation of Smad7 in streptozotocin-induced diabetic nephropathy.

AbstractBACKGROUND:
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.
AuthorsChenlin Gao, Keri Aqie, Jianhua Zhu, Guo Chen, Ling Xu, Lan Jiang, Yong Xu
JournalJournal of diabetes research (J Diabetes Res) Vol. 2014 Pg. 918396 ( 2014) ISSN: 2314-6753 [Electronic] Egypt
PMID24511554 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Fibronectins
  • Leupeptins
  • Proteasome Inhibitors
  • Smad7 Protein
  • Smad7 protein, rat
  • Tgfb1 protein, rat
  • Transforming Growth Factor beta1
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde
  • Streptozocin
  • Proteasome Endopeptidase Complex
  • Smurf2 protein, rat
  • Ubiquitin-Protein Ligases
Topics
  • Albuminuria (prevention & control)
  • Animals
  • Diabetic Nephropathies (drug therapy, metabolism, pathology)
  • Dose-Response Relationship, Drug
  • Fibronectins (antagonists & inhibitors, genetics, metabolism)
  • Gene Expression Regulation (drug effects)
  • Kidney (drug effects, metabolism, pathology, ultrastructure)
  • Leupeptins (administration & dosage, therapeutic use)
  • Male
  • Organ Size (drug effects)
  • Proteasome Endopeptidase Complex (metabolism)
  • Proteasome Inhibitors (administration & dosage, therapeutic use)
  • Proteolysis (drug effects)
  • Random Allocation
  • Rats
  • Rats, Wistar
  • Signal Transduction (drug effects)
  • Smad7 Protein (antagonists & inhibitors, genetics, metabolism)
  • Streptozocin
  • Transforming Growth Factor beta1 (antagonists & inhibitors, genetics, metabolism)
  • Ubiquitin-Protein Ligases (antagonists & inhibitors, chemistry, genetics, metabolism)
  • Ubiquitination (drug effects)

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