Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
Mol Med. 2011;17(11-12):1295-305. doi: 10.2119/molmed.2011.00131. Epub 2011 Aug 19.
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 × 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 1α (IRE1α)-JNK phosphorylation, protein kinase RNA-like endoplasmic reticulum kinase (PERK), eukaryotic translation initiation factor 2α subunit (eIF2α), 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.
内质网（ER）应激相关的细胞凋亡在损伤后器官重塑中发挥作用。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）染色和聚 ADP 核糖聚合酶在单侧输尿管梗阻（UUO）肾脏中的表达证实了肾细胞凋亡。通过 UUO 后葡萄糖调节蛋白 78（GRP78）和内质网滞留蛋白的共同赖氨酸-天冬氨酸-谷氨酸-亮氨酸（KDEL）基序的上调，诱发并证实了 ER 应激。在 UUO 肾脏中，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×蛋白（BAX）表达、半胱天冬氨酸蛋白酶-12 和 c-Jun N 末端激酶（JNK）磷酸化，被激活。持续的 ER 应激减弱了未剪接和剪接 X 盒结合蛋白 1（XBP-1）蛋白的表达，但继续激活肌醇需求 1α（IRE1α）-JNK 磷酸化、蛋白激酶 RNA 样内质网激酶（PERK）、真核翻译起始因子 2α 亚基（eIF2α）、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（cATF6）-CHOP 信号，诱导 ER 应激相关的细胞凋亡，但在 UUO 肾脏中减弱适应性未折叠蛋白反应。然而，在坎地沙坦治疗的 UUO 肾脏中，肾细胞凋亡和纤维化减轻。坎地沙坦与 XBP-1 表达的维持有关，并减弱了 ATF4、cATF6 和 CHOP 蛋白的表达。总之，结果表明，过度的 ER 应激导致肾小管细胞凋亡和随后的纤维化；坎地沙坦至少部分通过阻断 ER 应激相关的细胞凋亡来恢复肾脏完整性。减少 ER 应激可能是减轻肾脏纤维化的一种方法。
