Endoplasmic Reticulum Stress Implicated in the Development of Renal Fibrosis
Endoplasmic Reticulum Stress Implicated in the Development of Renal Fibrosis
复制标题
DOI：
10.2119/molmed.2011.00131
复制
发表时间：
2011-11-01
影响因子：
5.7
通讯作者：
Liu, Shing-Hwa
中科院分区：
文献类型：
--
作者：
Chiang, Chih-Kang;Hsu, Shih-Ping;Liu, Shing-Hwa
内质网（ER）应激相关的细胞凋亡在损伤后器官重塑中起作用。ER应激对肾小管损伤和纤维化的影响仍存在争议。本研究旨在探讨ER应激是否参与了体内肾小管破坏和间质纤维化。通过末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）染色和多聚ADP核糖聚合酶表达证实单侧输尿管梗阻（UUO）肾细胞凋亡。ER应激被诱发，并通过UUO后葡萄糖调节蛋白78（GRP 78）和ER滞留蛋白的共同Lys-Asp-Glu-Leu（KDEL）基序的上调来证实。ER应激相关的促凋亡信号，包括B细胞慢性淋巴细胞白血病（CLL）/淋巴瘤2相关x蛋白（BAX）表达，caspase-12和c-Jun N-末端激酶（JNK）磷酸化，在UUO肾中被激活。长时间的内质网应激减弱了非剪接和剪接的X-box结合蛋白1（XBP-1）蛋白的表达，但继续激活肌醇需要1 α，（IRE 1 α）-JNK磷酸化，蛋白激酶RNA样内质网激酶（PERK），真核翻译起始因子2 α亚基（eIF 2 α）、激活转录因子（ATF）-4、CCAAT/增强子结合蛋白（C/EBP）同源蛋白（CHOP）和切割激活转录因子6（cATF 6）-CHOP信号，其诱导ER应激相关的细胞凋亡，但减弱UUO肾中的适应性未折叠蛋白反应。然而，在坎地沙坦治疗的UUO肾中，肾细胞凋亡和纤维化减弱。坎地沙坦与XBP-1表达的维持和ATF 4、cATF 6和CHOP蛋白表达的减弱相关。两者合计，结果表明，压倒性的ER应激导致肾细胞凋亡和随后的纤维化;坎地沙坦，至少部分地，通过阻断ER应激相关的细胞凋亡，恢复肾脏的完整性。减少ER应激可能是减轻肾纤维化的一种方法。(C)2011 Feinstein医学研究所，www.feinsteininstitute.org在线地址：http://www.molmed.org doi：10.2119/molmed.2011.00131
Endoplasmic reticulum (ER) stress-associated apoptosis plays a role in organ remodeling after insult. The effect of ER stress on renal tubular damage and fibrosis remains controversial. This study aims to investigate whether ER stress is involved in tubular destruction and interstitial fibrosis in vivo. Renal cell apoptosis was proven by terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) stain and poly-ADP ribose polymerase expression in the unilateral ureteral obstruction (UUO) kidney. ER stress was evoked and confirmed by the upregulation of glucose-regulated protein 78 (GRP78) and the common Lys-Asp-Glu-Leu (KDEL) motif of ER retention proteins after UUO. ER stress-associated proapoptotic signals, including B-cell chronic lymphocytic leukemia (CLL)/lymphoma 2-associated x protein (BAX) expression, caspase-12 and c-Jun N-terminal kinase (JNK) phosphorylation, were activated in the UUO kidney. Prolonged ER stress attenuated both unsplicing and splicing X-box binding protein 1 (XBP-1) protein expression, but continued to activate inositol-requiring 1 alpha (IRE1 alpha)-JNK phosphorylation, protein kinase RNA-like endoplasmic reticulum kinase (PERK), eukaryotic translation initiation factor 2 alpha subunit (eIF2 alpha), activating transcription factor (ATF)-4, CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) and cleavage activating transcription factor 6 (cATF6)-CHOP signals, which induce ER stress-related apoptosis but attenuate adaptive unfolded protein responses in UUO kidneys. However, renal apoptosis and fibrosis were attenuated in candesartan-treated UUO kidney. Candesartan was associated with maintenance of XBP-1 expression and attenuated ATF4, cATF6 and CHOP protein expression. Taken together, results show that overwhelming ER stress leads to renal cell apoptosis and subsequent fibrosis; and candesartan, at least in part, restores renal integrity by blocking ER stress-related apoptosis. Reducing ER stress may present a way to attenuate renal fibrosis. (C) 2011 The Feinstein Institute for Medical Research, www.feinsteininstitute.org Online address: http://www.molmed.org doi: 10.2119/molmed.2011.00131