title: 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.affiliation: Department of Endocrinology, Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan 646000, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Endocrinology, Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan 646000, China ; Daping Hospital of Third Military Medical University, Chongqing 400042, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Endocrinology, Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan 646000, China.
authors.forename: Qinling
authors.initials: Q
authors.lastname: Nan
authors.affiliation: Department of Endocrinology, Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan 646000, China.
authors.forename: Chenlin
authors.initials: C
authors.lastname: Gao
authors.affiliation: Department of Endocrinology, Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan 646000, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Feng
authors.affiliation: Department of Endocrinology, Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan 646000, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Gou
authors.affiliation: Department of Endocrinology, Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan 646000, China.
authors.forename: Guo
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Endocrinology, Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan 646000, China.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology, Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan 646000, China.
authors.forename: Pijun
authors.initials: P
authors.lastname: Yan
authors.affiliation: Department of Endocrinology, Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan 646000, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Endocrinology, Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan 646000, China.
authors.forename: Yong
authors.identifier: 0000-0002-9534-6252
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000818:Animals; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D015536:Down-Regulation / Q000187:drug effects; D005947:Glucose / Q000633:toxicity; D007677:Kidney Function Tests; D007678:Kidney Glomerulus / Q000473:pathology; D007976:Leupeptins / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D011507:Proteinuria / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D059748:Proteolysis / Q000187:drug effects*; D017208:Rats, Wistar; D013311:Streptozocin; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D007976:Leupeptins; D009419:Nerve Tissue Proteins; D061988:Proteasome Inhibitors; C511209:Skil_v1 protein, rat; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D013311:Streptozocin; D005947:Glucose; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde