Defective interplay between mTORC1 activity and endoplasmic reticulum stress-unfolded protein response in uremic vascular calcification

Vascular calcification increases the risk of cardiovascular disease and death in patients with chronic kidney disease (CKD). Increased activity of the mammalian target of rapamycin complex 1 (mTORC1) and endoplasmic reticulum (ER) stress-unfolded protein response (UPR) are reported to partake independently 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) or 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 (Sesn)1 and Sesn3 feeding back to inhibit mTORC1. Activating transcription factor 4 (ATF4) arising from the UPR mediates cell death via expression of CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP)...