Ubiquitin C-terminal hydrolase-L5 is required for high glucose-induced transforming growth factor-β receptor I expression and hypertrophy in mesangial cells.

Transforming growth factor-β (TGF-β) is pivotal in the pathogenesis of diabetic nephropathy. Type 1 TGF-β receptor (TGF-βR1) is degraded by Smad7-dependent ubiquitination-proteasomal pathway, which is deubiquitinated by ubiquitin C-terminal hydrolase-L5 (UCHL5). Therefore, we studied the role of UCHL5 in high glucose (27.8mM)-induced TGF-βR1 protein expression in mouse mesangial (MES13) cells. UCHL5 short hairpin RNA (shRNA) was used to knock down UCHL5 while LY294002 and the dominant-negative p85 were used to inhibit phosphatidylinositol-3-kinase (PI3K). We found that high glucose increased phospho-Akt, TGF-βR1 mRNA and protein expression. High glucose also increased UCHL5 protein expression, which was attenuated by LY294002, the dominant-negative p85 and the dominant-negative CREB. High glucose-induced TGF-βR1 protein expression and TGF-βR1 protein deubiquitination were attenuated by UCHL5 shRNA. Additionally, high glucose-induced p21(WAF1), fibronectin protein expression and cell hypertrophy were attenuated by UCHL5 shRNA. However, high glucose-induced TGF-βR1 mRNA, p27(kip1) protein expression and growth inhibition were not affected by UCHL5 shRNA. Finally, glomerular UCHL5 and TGF-βR1 protein expression were increased in streptozotocin-diabetic rats at 8weeks. We conclude that PI3K-dependent UCHL5 is required for high glucose-induced TGF-βR1 protein expression in mesangial cells. UCHL5 is also required for high glucose-induced TGF-βR1 protein deubiquitination, p21(WAF1) and fibronectin protein expression and cell hypertrophy. Copyright © 2013 Elsevier Inc. All rights reserved.

Citation

Yu-Min Ko, Chun-Ying Chang, Shean-Jaw Chiou, Fu-Jie Hsu, Jau-Shyang Huang, Yu-Lin Yang, Jinn-Yuh Guh, Lea-Yea Chuang. Ubiquitin C-terminal hydrolase-L5 is required for high glucose-induced transforming growth factor-β receptor I expression and hypertrophy in mesangial cells. Archives of biochemistry and biophysics. 2013 Jul 15;535(2):177-86

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PMID: 23500140

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