The inhibitory effect of quercetin on asymmetric dimethylarginine-induced apoptosis is mediated by the endoplasmic reticulum stress pathway in glomerular endothelial cells.
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.
Department of Nephrology, Beijing Friendship Hospital, Faculty of Kidney Diseases, Capital Medical University, Beijing 100050, China. gwk0777@gmail.com.
Weikang
W
Guo
Department of Nephrology, Beijing Friendship Hospital, Faculty of Kidney Diseases, Capital Medical University, Beijing 100050, China. mattding@163.com.
Jiaxiang
J
Ding
Department of Nephrology, Beijing Friendship Hospital, Faculty of Kidney Diseases, Capital Medical University, Beijing 100050, China. zhah0351@126.com.
Aihua
A
Zhang
Department of Nephrology, Beijing Friendship Hospital, Faculty of Kidney Diseases, Capital Medical University, Beijing 100050, China. dianadwd@163.com.
Wendi
W
Dai
Department of Nephrology, Beijing Friendship Hospital, Faculty of Kidney Diseases, Capital Medical University, Beijing 100050, China. liusha201304@163.com.
Sha
S
Liu
Department of Nephrology, Beijing Friendship Hospital, Faculty of Kidney Diseases, Capital Medical University, Beijing 100050, China. diaoted@163.com.
Zongli
Z
Diao
Department of Nephrology, Beijing Friendship Hospital, Faculty of Kidney Diseases, Capital Medical University, Beijing 100050, China. wangliyan7731@sina.com.
Liyan
L
Wang
Department of Nephrology, Beijing Friendship Hospital, Faculty of Kidney Diseases, Capital Medical University, Beijing 100050, China. whysnowman@126.com.
Xue
X
Han
Department of Nephrology, Beijing Friendship Hospital, Faculty of Kidney Diseases, Capital Medical University, Beijing 100050, China. nephro@ccmu.edu.cn.
Wenhu
W
Liu
D017209:Apoptosis / Q000187:drug effects*; D001120:Arginine / Q000031:analogs & derivatives* / Q000633:toxicity; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004722:Endoribonucleases / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051742:Transcription Factor CHOP / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
D001120:Arginine; D004722:Endoribonucleases; D048031:JNK Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011794:Quercetin; D034741:RNA, Small Interfering; D051742:Transcription Factor CHOP; D016212:Transforming Growth Factor beta; D019892:eIF-2 Kinase; C497249:DDIT3 protein, human; C018524:N,N-dimethylarginine; C528229:ERN1 protein, human