Involvement of Endoplasmic Reticulum Stress, Autophagy, and Apoptosis in Advanced Glycation End Products-Induced Glomerular Mesangial Cell Injury.
Advanced glycation end-products (AGEs)-induced mesangial cell death is one of major causes of glomerulus dysfunction in diabetic nephropathy. Both endoplasmic reticulum (ER) stress and autophagy are adaptive responses in cells under environmental stress and participate in the renal diseases. The role of ER stress and autophagy in AGEs-induced mesangial cell death is still unclear. Here, we investigated the effect and mechanism of AGEs on glomerular mesangial cells. AGEs dose-dependently decreased mesangial cell viability and induced cell apoptosis. AGEs also induced ER stress signals in a time- and dose-dependent manner. Inhibition of ER stress with 4-phenylbutyric acid effectively inhibited the activation of eIF2α and CHOP signals and reversed AGEs-induced cell apoptosis. AGEs also activated LC-3 cleavage, increased Atg5 expression, and decreased p62 expression, which indicated the autophagy induction in mesangial cells. Inhibition of autophagy by Atg5 siRNAs transfection aggravated AGEs-induced mesangial cell apoptosis. Moreover, ER stress inhibition by 4-phenylbutyric acid significantly reversed AGEs-induced autophagy, but autophagy inhibition did not influence the AGEs-induced ER stress-related signals activation. These results suggest that AGEs induce mesangial cell apoptosis via an ER stress-triggered signaling pathway. Atg5-dependent autophagy plays a protective role. These findings may offer a new strategy against AGEs toxicity in the kidney.
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Integrated Diagnostics &Therapeutics, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan.
Chih-Kang
CK
Chiang
Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
Ching-Chia
CC
Wang
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Tien-Fong
TF
Lu
Department of Urology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Kuo-How
KH
Huang
Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
Meei-Ling
ML
Sheu
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.|Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
Shing-Hwa
SH
Liu
Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
Kuan-Yu
KY
Hung
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