The proteasome inhibitor, MG132, attenuates diabetic nephropathy by inhibiting SnoN degradation in vivo and in vitro.

Abstract

Transforming growth factor-β (TGF-β) has been shown to be involved in diabetic nephropathy (DN). The SnoN protein can regulate TGF-β signaling through interaction with Smad proteins. Recent studies have shown that SnoN is mainly degraded by the ubiquitin-proteasome pathway. However, the role of SnoN in the regulation of TGF- β/Smad signaling in DN is still unclear. In this study, diabetic rats were randomly divided into a diabetic control group (DC group) and a proteasome inhibitor (MG132) diabetes therapy group (DT group). Kidney damage parameters and the expression of SnoN, Smurf2, and TGF-β were observed. Simultaneously, we cultured rat glomerular mesangial cells (GMCs) stimulated with high glucose, and SnoN and Arkadia expression were measured. Results demonstrated that 24-hour urine protein, ACR, BUN, and the expression of Smurf2 and TGF- β were significantly increased (P < 0.05), whereas SnoN was significantly decreased in the DC group (P < 0.05). However, these changes diminished after treatment with MG132. SnoN expression in GMCs decreased significantly (P < 0.05), but Arkadia expression gradually increased due to high glucose stimulation (P < 0.05), which could be almost completely reversed by MG132 (P < 0.05). The present results support the hypothesis that MG132 may alleviate kidney damage by inhibiting SnoN degradation and TGF-β activation, suggesting that the ubiquitin-proteasome pathway may become a new therapeutic target for DN.

• Authors: Wei Huang, Chen Yang, Qinling Nan, Chenlin Gao, Hong Feng, Fang Gou, Guo Chen, Zhihong Zhang, Pijun Yan, Juan Peng, Yong Xu
• Journal: BioMed research international (Biomed Res Int) Vol. 2014 Pg. 684765 ( 2014) ISSN: 2314-6141 [Electronic] United States
• PMID: 25003128 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Leupeptins
• Nerve Tissue Proteins
• Proteasome Inhibitors
• Skil_v1 protein, rat
• Transcription Factors
• Transforming Growth Factor beta
• Streptozocin
• Glucose
• benzyloxycarbonylleucyl-leucyl-leucine aldehyde

Topics

• Animals
• Diabetic Nephropathies (drug therapy, metabolism, physiopathology)
• Down-Regulation (drug effects)
• Glucose (toxicity)
• Kidney Function Tests
• Kidney Glomerulus (pathology)
• Leupeptins (pharmacology, therapeutic use)
• Male
• Mesangial Cells (drug effects, metabolism, pathology)
• Nerve Tissue Proteins (metabolism)
• Proteasome Inhibitors (pharmacology, therapeutic use)
• Proteinuria (complications, pathology, physiopathology)
• Proteolysis (drug effects)
• Rats, Wistar
• Streptozocin
• Transcription Factors (metabolism)
• Transforming Growth Factor beta (metabolism)