Division of Nephrology, Department of Medicine and Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University , Montreal, Quebec , Canada.
Division of Endocrinology and Metabolism, Department of Medicine and Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University , Montreal, Quebec , Canada.
Am J Physiol Renal Physiol. 2018 Jun 1;314(6):F1046-F1061. doi: 10.1152/ajprenal.00350.2017. Epub 2018 Jan 10.
Vascular calcification increases the risk of cardiovascular disease and death in patients with chronic kidney disease (CKD). Increased activity of mammalian target of rapamycin complex 1 (mTORC1) and endoplasmic reticulum (ER) stress-unfolded protein response (UPR) are independently reported to partake in the pathogenesis of vascular calcification in CKD. However, the association between mTORC1 activity and ER stress-UPR remains unknown. We report here that components of the uremic state [activation of the receptor for advanced glycation end products (RAGE) and hyperphosphatemia] potentiate vascular smooth muscle cell (VSMC) calcification by inducing persistent and exaggerated activity of mTORC1. This gives rise to prolonged and excessive ER stress-UPR as well as attenuated levels of sestrin 1 ( Sesn1) and Sesn3 feeding back to inhibit mTORC1 activity. Activating transcription factor 4 arising from the UPR mediates cell death via expression of CCAAT/enhancer-binding protein (c/EBP) homologous protein (CHOP), impairs the generation of pyrophosphate, a potent inhibitor of mineralization, and potentiates VSMC transdifferentiation to the osteochondrocytic phenotype. Short-term treatment of CKD mice with rapamycin, an inhibitor of mTORC1, or tauroursodeoxycholic acid, a bile acid that restores ER homeostasis, normalized mTORC1 activity, molecular markers of UPR, and calcium content of aortas. Collectively, these data highlight that increased and/or protracted mTORC1 activity arising from the uremic state leads to dysregulated ER stress-UPR and VSMC calcification. Manipulation of the mTORC1-ER stress-UPR pathway opens up new therapeutic strategies for the prevention and treatment of vascular calcification in CKD.
血管钙化增加了慢性肾脏病（CKD）患者心血管疾病和死亡的风险。哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）和内质网（ER）应激未折叠蛋白反应（UPR）活性的增加被独立报道参与了 CKD 血管钙化的发病机制。然而，mTORC1 活性和 ER 应激-UPR 之间的关联尚不清楚。我们在这里报告，尿毒症状态的成分[晚期糖基化终产物（RAGE）受体的激活和高磷血症]通过诱导 mTORC1 的持续和过度激活，增强血管平滑肌细胞（VSMC）钙化。这导致延长和过度的 ER 应激-UPR 以及 sestrin 1（Sesn1）和 Sesn3 的水平降低，反馈抑制 mTORC1 活性。UPR 产生的激活转录因子 4 通过表达 CCAAT/增强子结合蛋白（c/EBP）同源蛋白（CHOP）介导细胞死亡，损害焦磷酸盐的产生，焦磷酸盐是一种有效的矿化抑制剂，并增强 VSMC 向成骨软骨细胞表型的转化。用雷帕霉素（mTORC1 的抑制剂）或牛磺熊脱氧胆酸（一种恢复 ER 动态平衡的胆汁酸）短期治疗 CKD 小鼠，可使 mTORC1 活性、UPR 的分子标志物和主动脉的钙含量正常化。总的来说，这些数据强调了尿毒症状态引起的 mTORC1 活性的增加和/或持续时间延长导致 ER 应激-UPR 和 VSMC 钙化的失调。对 mTORC1-ER 应激-UPR 途径的操纵为预防和治疗 CKD 中的血管钙化开辟了新的治疗策略。
