Early activation of endoplasmic reticulum stress is associated with arginine-induced acute pancreatitis

Abstract

Endoplasmic reticulum (ER) stress mechanisms have been found to play critical roles in a number of diseases states, such as diabetes mellitus and Alzheimer disease, but whether they are involved in acute pancreatitis is unknown. Here we show for the first time that all major ER stress sensing and signaling mechanisms are present in exocrine acini and are activated early in the arginine model of experimental acute pancreatitis. Pancreatitis was induced in rats by intraperitoneal injection of 4.0 g/kg body wt arginine. Pancreatitis severity was assessed by analysis of serum amylase, pancreatic trypsin activity, water content, and histology. ER stress-related molecules PERK, eIF2alpha, ATF6, XBP-1, BiP, CHOP, and caspase-12 were analyzed. Arginine treatment induced rapid and severe pancreatitis, as indicated by increased serum amylase, pancreatic tissue edema, and acinar cell damage within 4 h. Arginine treatment also caused an early activation of ER stress, as indicated by phosphorylation of PERK and its downstream target eIF2alpha, ATF6 translocation into the nucleus (within 1 h), and upregulation of BiP (within 4 h). XBP-1 splicing and CHOP expression were observed within 8 h. After 24 h, increased activation of the ER stress-related proapoptotic molecule caspase-12 was observed along with an increase in caspase-3 activity and TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labeling (TUNEL) staining in exocrine acini. These results indicate that ER stress is an important early acinar cell event that likely contributes to the development of acute pancreatitis in the arginine model.

MIST1 Links Secretion and Stress as both Target and Regulator of the Unfolded Protein Response

“…In the case of unresolvable stress, the UPR can activate a proapoptotic program and trigger cell death, thus requiring cells to maintain tight control over the master regulators and their associated target genes. Indeed, disruption of the UPR and its corresponding response pathways has been linked to cancer progression as well as to other human diseases (4)(5)(6)(7), highlighting the need to discover new regulatory and effector UPR mechanisms that can be exploited in designing strategic biotherapeutics.…”

Tauroursodeoxycholic acid reduces endoplasmic reticulum stress, trypsin activation, and acinar cell apoptosis while increasing secretion in rat pancreatic acini

“…This includes dilatation or vacuolation of the ER and loss of membrane-bound ribosomes (1,17,25,27). ER changes seem a common reaction of acini to the induction of ER stress (18,23). Key regulators of the ER stress response are altered during AP and several ER-resident chaperones are upregulated.…”

Pancreatic Protein Tyrosine Phosphatase 1B Deficiency Exacerbates Acute Pancreatitis in Mice

“…16 The mechanism by which PTP1B deficiency potentiates MAPK signaling remains unknown, but can be indirect and related to increased inflammation. Last, ER stress is implicated in the pathophysiology of pancreatitis, 53,67 and attenuation of ER stress by chemical chaperones mitigates the disease in animal models. 54 Increased PERK and IRE1a activation in PTP1B knockout mice and inhibitor-treated acinar cells is consistent with previous findings of enhanced PERK and IRE1a signaling in MIN6 b-cells.…”

“…Unfolded protein response is used by cells to counter the deleterious effects of ER stress and is triggered by transmembrane sensors, such as PKR-like ER-regulated kinase (PERK), that detect unfolded proteins in the ER and convey information through their cytosolic domain. 52 More important, activation of ER stress is associated with AP 53 and treatment with ER chaperones mitigates the disease in animal models. 54 In addition, we previously demonstrated that PTP1B knockdown in MIN6 b-cells enhanced PERK and inositol requiring enzyme 1a (IRE1a) signaling.…”