Albumin Overload Induces Apoptosis in Renal Tubular Epithelial Cells through a CHOP-Dependent Pathway
Albumin Overload Induces Apoptosis in Renal Tubular Epithelial Cells through a CHOP-Dependent Pathway
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DOI：
10.1089/omi.2009.0073
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发表时间：
2010-02-01
影响因子：
3.3
通讯作者：
Zhang, Jianguo
中科院分区：
文献类型：
--
作者：
Wu, Xiaowei;He, Yani;Zhang, Jianguo
蛋白尿诱导的近端肾小管上皮细胞(PTCs)凋亡在慢性肾脏疾病肾小管间质损伤中起重要作用。最近的研究表明，内质网应激参与了蛋白尿诱导的PTCs的凋亡。我们的研究表明，蛋白尿患者白蛋白超负荷导致内质网应激、CCAAT/增强子结合蛋白同源蛋白(CHOP)、PKR样激酶(PERK)激活和PTCs凋亡。肾病患者肾脏近端肾小管上皮细胞的凋亡指数约为对照组的13倍。肾组织中GRP78、ORP150和CHOP的表达增加，并可见CHOP的核定位。GRP78、CHOP、PERK和磷酸化PERK的表达与HSA超载成比例增加，且呈剂量和时间依赖关系。SiRNA下调CHOP可显著降低HSA诱导的HKC凋亡。PERK的表达无明显变化，但磷酸化增加。此外，PERK基因的敲除显著抑制了HSA诱导的CHOP表达，与对照组相比，抑制了HKCs的2.48倍的凋亡。CHOP过表达可促进白蛋白诱导的HKC凋亡，但对PERK的表达无明显影响，而PERK的磷酸化水平降低。我们的数据表明，蛋白尿诱导了肾小管细胞的内质网应激，这可能随后通过依赖于perk-chop的途径导致肾小管损伤。这种内质网应激诱导的细胞凋亡通路可能参与了慢性肾脏疾病蛋白尿对肾小管间质的损伤。
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.