Department of Nephrology, Daping Hospital , the Third Military Medical University, Chongqing 400042, People's Republic of China.
OMICS. 2010 Feb;14(1):61-73. doi: 10.1089/omi.2009.0073.
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.
蛋白尿诱导的近端肾小管细胞 (PTC) 凋亡在慢性肾脏病的肾小管间质损伤中起关键作用。最近的研究表明，内质网 (ER) 应激参与了蛋白尿诱导的 PTC 凋亡。我们的研究表明，白蛋白过载导致 ER 应激、CCAAT/增强子结合蛋白同源蛋白 (CHOP) 和蛋白激酶 R 样激酶 (PERK) 的激活，并导致蛋白尿患者的 PTC 凋亡。肾病患者近端肾小管细胞的凋亡指数比对照肾脏高约 13 倍。还检测到肾病患者中 GRP78、ORP150 和 CHOP 的肾小管表达增加和 CHOP 的核定位。GRP78、CHOP、PERK 和磷酸化 PERK 的表达随白蛋白过载呈剂量和时间依赖性增加。用 siRNA 敲低 CHOP 可显著减少 HSA 诱导的 HKC 凋亡。PERK 的表达没有明显变化，但 PERK 的磷酸化增加。此外，PERK 的敲低显著抑制了 HSA 诱导的 CHOP 表达，与对照组相比，HKC 的凋亡抑制了 2.48 倍。CHOP 的过表达增强了白蛋白诱导的 HKC 凋亡，PERK 的表达没有明显差异，而 PERK 的磷酸化减少。我们的数据表明，蛋白尿诱导肾小管细胞内质网应激，这可能通过 PERK-CHOP 依赖性途径导致肾小管损伤。这种 ER 应激诱导的凋亡途径可能通过蛋白尿导致慢性肾脏病的肾小管间质损伤。
