中文摘要：

目的：探讨过度内质网应激在慢性环孢素A（ CsA）肾毒性细胞凋亡中的作用机制。方法：将Spra-gue-Dawley大鼠分为正常对照组和慢性CsA肾毒性组，分别给予皮下注射橄榄油（1 mg·kg^-1· d^-1）和CsA （15 mg· mg·kg^-1· d^-1）1周或4周后处死大鼠。三色染色和TUNEL染色观察肾小管间质纤维化和细胞凋亡；免疫组织化学染色和免疫印迹检测免疫球蛋白结合蛋白（ BiP）、磷酸化的真核细胞翻译起始因子2α（ eIF2α）、生长阻滞及DNA损伤诱导蛋白153（GADD153）、caspase-12和caspase-3蛋白表达。结果： CsA注射1周观察不到肾小管间质纤维化和TUNEL阳性细胞，而给予CsA注射4周大鼠表现为明显的肾小管间质纤维化[（38．9±3．3）％vs （0．0±0．0）％， P＜0．01]和大量TUNEL阳性细胞[（89±9）％ vs （7±2）％， P＜0．01]。与对照组比较，CsA组BiP和caspase-12蛋白的表达于1周达到高峰，4周后降至正常水平；反之，eIF2α和caspase-3蛋白表达呈时间依赖性增加。结论：在慢性CsA肾毒性中，过度的内质网应激耗尽分子伴侣，激活凋亡途径，从而导致肾小管上皮细胞凋亡和肾小管间质损伤。

英文摘要：

AIM：To investigate the impact of excessive endoplasmic reticulum stress on apoptotic cell death in a rat model of chronic cyclosporine A （ CsA ） nephrotoxicity .METHODS： Male Sprague-Dawley rats on a low-salt diet were subcutaneously injected with vehicle （olive oil, 1 mL· mg·kg^-1· d^-1） or CsA （15 mg/kg） daily for 1 or 4 weeks.Tubulointerstitial fibrosis and apoptotic cell death were estimated by trichrome staining and TUNEL staining .In addition , immunohistochemistry and immunoblotting were used to evaluate the expression of immunoglobulin -binding protein （ BiP） , eukaryotic initiation factor 2α（eIF2α）, growth arrest and DNA damage-inducible protein 153 （GADD153）, caspase-12 and caspase-3.RESULTS：The rats treated with CsA for 1 week did not develop tubulointerstitial fibrosis and TUNEL-positive cells, whereas 4-week treatment with CsA induced typical tubulointerstitial fibrosis and increased TUNEL-positive cells. CsA induced a significant increase in BiP and caspase-12 expression peaked at 1 week, and then returned to normal levels at 4 weeks.In contrast, the expression of eIF2α, GADD153 and caspase-3 in CsA-treated rat kidneys were significantly increased in a time-dependent manner .CONCLUSION：Excessive endoplasmic reticulum stress causes apoptotic cell death by depleting molecular chaperones and stimulating the proapoptotic pathway in chronic CsA nephrotoxicity .