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

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.

Involvement of Increased Endogenous Asymmetric Dimethylarginine in the Hepatic Endoplasmic Reticulum Stress of Type 2 Diabetic Rats

“…These results further indicate that increased endogenous ADMA plays a crucial role in the stimulation of hepatic ER stress in type 2 diabetic rats. Recently, ADMA-induced ER stress also found in cultured lung epithelial cells [35], endothelial cells [36] and 3T3-L1 adipocytes [37]. Furthermore, some well-known factors to elevate endogenous ADMA such as homocysteine [38], free fatty acid [1], [39] and high glucose [40] could induce endoplasmic reticulum stress.…”

Endoplasmic reticulum stress in kidney function and disease

“…N-acetylcysteine also attenuated osmolar contrast-induced apoptosis of renal tubular cells by decreasing ROS levels and ER stress [31]. Similarly, flavonoids such as baicalin and quescetin reduced ER and oxidative stress, and they also ameliorated ischemia-reperfusion injury [32] or asymmetric dimethylarginine-induced apoptosis in glomerular endothelial cells [33]. Thus, antioxidative reagents can relieve some renal diseases by suppressing ER stress.…”

Emerging Liver–Kidney Interactions in Nonalcoholic Fatty Liver Disease

“…Molecular mechanisms underlying ADMA elevation in CKD include both and increased ADMA production by PRMT and impaired ADMA catabolism by hepatic and renal DDAH, the latter being the predominant factor and a strong predictor of CKD [125]. Several pharmacological agents evaluated in preclinical/Phase IIb studies hold promise to neutralize the deleterious effects of ADMA in NAFLD and CKD, including pentoxifylline [126], quercetin [127], and the FXR agonist obeticholic acid [128], but their impact on clinical endpoints has yet to be assessed.…”

“…Hepatic steatosis and necroinflammation Insulin resistance Glomerular/tubule-interstitial ischemia and sclerosis Quercetin, pentoxifylline, FXR agonist obeticholic acid [126][127][128] 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1)…”