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Int. J. Mol. Sci. 2014, 15(1), 484-503; doi:10.3390/ijms15010484
Article

The Inhibitory Effect of Quercetin on Asymmetric Dimethylarginine-Induced Apoptosis Is Mediated by the Endoplasmic Reticulum Stress Pathway in Glomerular Endothelial Cells

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Department of Nephrology, Beijing Friendship Hospital, Faculty of Kidney Diseases, Capital Medical University, Beijing 100050, China
* Author to whom correspondence should be addressed.
Received: 10 October 2013 / Revised: 12 December 2013 / Accepted: 16 December 2013 / Published: 2 January 2014
(This article belongs to the collection Programmed Cell Death and Apoptosis)
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Abstract

Asymmetric dimethylarginine (ADMA) is considered an independent mortality and cardiovascular risk factor in chronic kidney disease (CKD) patients, and contributes to the development of renal fibrosis. Quercetin (QC), a natural component of foods, protects against renal injury. Here, we explored the possible mechanisms that are responsible for ADMA-induced renal fibrosis and the protective effect of QC. We found that ADMA treatment activated the endoplasmic reticulum (ER) stress sensor proteins phosphorylated protein kinase RNA-activated-like ER kinase (PERK) and inositol requiring-1α (IRE1), which correspondingly induced C/EBP homologous protein (CHOP) expression and phosphorylated c-Jun N-terminal kinase (JNK) phosphorylation in glomerular endothelial cells (GEnCs). Following this, ADMA promoted ER stress-induced apoptosis and resulted in transforming growth factor β (TGF-β) expression in GEnCs. SP600125, an inhibitor of JNK, and CHOP siRNA protected against ADMA-induced cell apoptosis and TGF-β expression. QC prevented ADMA-induced PERK and IRE1 apoptotic ER stress pathway activation. Also, ADMA-induced GEnCs apoptosis and TGF-β expression was reduced by QC. Overexpression of CHOP blocked QC-mediated protection from apoptosis in ER stressed cells. Overall, these observations indicate that ADMA may induce GEnCs apoptosis and TGF-β expression by targeting the PERK-CHOP and IRE1-JNK pathway. In addition, drugs such as QC targeting ER stress may hold great promise for the development of novel therapies against ADMA-induced renal fibrosis.
Keywords: ER stress; apoptosis; ADMA; TGF-β; quercetin ER stress; apoptosis; ADMA; TGF-β; quercetin
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Guo, W.; Ding, J.; Zhang, A.; Dai, W.; Liu, S.; Diao, Z.; Wang, L.; Han, X.; Liu, W. The Inhibitory Effect of Quercetin on Asymmetric Dimethylarginine-Induced Apoptosis Is Mediated by the Endoplasmic Reticulum Stress Pathway in Glomerular Endothelial Cells. Int. J. Mol. Sci. 2014, 15, 484-503.

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