Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA.
Sci Rep. 2017 Feb 23;7:43152. doi: 10.1038/srep43152.
Endothelin-1 (ET-1) promotes renal damage during cardiovascular disease; yet, the molecular mechanisms involved remain unknown. Endoplasmic reticulum (ER) stress, triggered by unfolded protein accumulation in the ER, contributes to apoptosis and organ injury. These studies aimed to determine whether the ET-1 system promotes renal ER stress development in response to tunicamycin. ET deficient (ET def) or transgenic control (TG-con) rats were used in the presence or absence of ET receptor antagonism. Tunicamycin treatment similarly increased cortical ER stress markers in both rat genotypes; however, only ET def rats showed a 14-24 fold increase from baseline for medullary GRP78, sXBP-1, and CHOP. Pre-treatment of TG-con rats with the ET blocker ABT-627 for 1 week prior to tunicamycin injection significantly reduced the ER stress response in cortex and medulla, and also inhibited renal apoptosis. Pre-treatment with ABT-627 failed to decrease renal ER stress and apoptosis in ET def rats. In conclusion, the ET-1 system is important for the development of tunicamycin-induced renal ER stress and apoptosis. ET receptor activation induces renal ER stress genes and apoptosis, while functional activation of the ET receptor has protective effects. These results highlight targeting the ET receptor as a therapeutic approach against ER stress-induced kidney injury.
内皮素-1（ET-1）在心血管疾病期间促进肾脏损伤；然而，涉及的分子机制仍不清楚。内质网（ER）应激是由 ER 中未折叠蛋白积累引发的，导致细胞凋亡和器官损伤。这些研究旨在确定 ET-1 系统是否会促进肾 ER 应激的发展，以响应衣霉素。在存在或不存在 ET 受体拮抗剂的情况下，使用 ET 缺乏（ET def）或转基因对照（TG-con）大鼠。衣霉素处理同样增加了两种大鼠基因型的皮质 ER 应激标志物；然而，只有 ET def 大鼠的髓质 GRP78、sXBP-1 和 CHOP 的基线增加了 14-24 倍。在注射衣霉素前，用 ET 阻滞剂 ABT-627 预处理 TG-con 大鼠 1 周，显著降低了皮质和髓质的 ER 应激反应，并抑制了肾细胞凋亡。ABT-627 预处理未能减少 ET def 大鼠的肾 ER 应激和凋亡。总之，ET-1 系统对衣霉素诱导的肾 ER 应激和凋亡的发展很重要。ET 受体的激活诱导了肾 ER 应激基因和细胞凋亡，而 ET 受体的功能激活具有保护作用。这些结果强调了靶向 ET 受体作为一种治疗 ER 应激诱导的肾损伤的方法。
