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

Abstract

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.

• Authors: Chenlin Gao, Keri Aqie, Jianhua Zhu, Guo Chen, Ling Xu, Lan Jiang, Yong Xu
• Journal: Journal of diabetes research (J Diabetes Res) Vol. 2014 Pg. 918396 ( 2014) ISSN: 2314-6753 [Electronic] England
• PMID: 24511554 (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
• Streptozocin
• Smurf2 protein, rat
• Ubiquitin-Protein Ligases
• Proteasome Endopeptidase Complex
• benzyloxycarbonylleucyl-leucyl-leucine aldehyde

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)