UPR regulation by the Thbd-PC system. (A) Schematic illustration of Thbd-dependent PC activation on endothelial cells and of molecular defects in employed mouse models with altered Thbd-dependent PC activation. (B-E) Representative immunoblots (B) and bar graphs (C-E) showing nuclear levels of ER transcription factors in renal cortex samples 26 weeks post STZ treatment. (F) Restoring aPC levels or inhibition of ER stress with the chemical chaperone TUDCA or deletion of CHOP (CHOP^−/− mice) protects Thbd^Pro/Pro mice against DKD. Dot plot summarizing albuminuria. C, nondiabetic control mice; DM, diabetic mice; EPCR, endothelial protein C receptor. Mean ± SEM of at least 6 (C-E) or 8 (F) mice per group. *P < .05; **P < .01 (C-E: ANOVA).