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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.
AuthorsWei Huang, Chen Yang, Qinling Nan, Chenlin Gao, Hong Feng, Fang Gou, Guo Chen, Zhihong Zhang, Pijun Yan, Juan Peng, Yong Xu
JournalBioMed research international (Biomed Res Int) Vol. 2014 Pg. 684765 ( 2014) ISSN: 2314-6141 [Electronic] United States
PMID25003128 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Leupeptins
  • Nerve Tissue Proteins
  • Proteasome Inhibitors
  • SnoN protein, rat
  • Transcription Factors
  • Transforming Growth Factor beta
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde
  • Streptozocin
  • Glucose
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)

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