Albumin overload induces apoptosis in renal tubular epithelial cells through a CHOP-dependent pathway.
The proteinuria-induced apoptosis of proximal tubular cells (PTCs) plays a crucial role in renal tubulointerstitial injury in chronic kidney disease. Recent studies have shown that endoplasmic reticulum (ER) stress is involved in proteinuria-induced apoptosis of PTCs. Our study showed that albumin overload led to ER stress, CCAAT/enhancer-binding protein-homologous protein (CHOP), and PKR-like kinase (PERK) activation and to apoptosis of PTCs in proteinuria patients. The apoptotic index of proximal renal tubular cells in the nephrotic kidneys was about 13-fold higher than that in control kidneys. The increased tubular expression of GRP78, ORP150, and CHOP and nuclear localization of CHOP in nephrotic kidneys were also detected. The expression of GRP78, CHOP, PERK, and phosphorylated PERK increased proportionately with HSA overload in a dose- and time-dependent manner. Knockdown of CHOP by siRNA significantly reduced the HSA-induced apoptosis of HKC. The expression of PERK did not significantly change, but the phosphorylation of PERK increased. Furthermore, knockdown of PERK significantly inhibited HSA-induced CHOP expression, suppressing apoptosis in HKCs by 2.48-fold compared to controls. Overexpression of CHOP enhanced the apoptosis of HKC induced by albumin, no significant difference was observed in the expression of PERK, whereas the phosphorylation of PERK decreased. Our data indicated that proteinuria induces ER stress in renal tubular cells, which may subsequently lead to tubular damage through a PERK-CHOP-dependent pathway. This ER stress-induced apoptosis pathway may contribute to renal tubulointerstitial injury by proteinuria in chronic kidney disease.
Wu
Xiaowei
X
Department of Nephrology, Daping Hospital , the Third Military Medical University, Chongqing 400042, People's Republic of China.
He
Yani
Y
Jing
Yu
Y
Li
Kailong
K
Zhang
Jianguo
J
D000328:Adult; D000418:Albumins / Q000378:metabolism*; D017209:Apoptosis; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D016022:Case-Control Studies; D017931:DNA Primers; D000091342:Endoplasmic Reticulum Chaperone BiP; D004847:Epithelial Cells / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007684:Kidney Tubules / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering
D000418:Albumins; D022762:CCAAT-Enhancer-Binding Proteins; D017931:DNA Primers; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D034741:RNA, Small Interfering