Endoplasmic reticulum stress is chronically activated in chronic pancreatitis

Raghuwansh P Sah; Sushil K Garg; Ajay K Dixit; Vikas Dudeja; Rajinder K Dawra; Ashok K Saluja

doi:10.1074/jbc.M113.528174

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Endoplasmic reticulum stress is chronically activated in chronic pancreatitis

Journal article

Open access

Peer reviewed

Endoplasmic reticulum stress is chronically activated in chronic pancreatitis

Raghuwansh P Sah, Sushil K Garg, Ajay K Dixit, Vikas Dudeja, Rajinder K Dawra and Ashok K Saluja

The Journal of biological chemistry, Vol.289(40), pp.27551-27561

10/03/2014

DOI: 10.1074/jbc.M113.528174

PMID: 25077966

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Abstract

The pathogenesis of chronic pancreatitis (CP) is poorly understood. Endoplasmic reticulum (ER) stress has now been recognized as a pathogenic event in many chronic diseases. However, ER stress has not been studied in CP, although pancreatic acinar cells seem to be especially vulnerable to ER dysfunction because of their dependence on high ER volume and functionality. Here, we aim to investigate ER stress in CP, study its pathogenesis in relation to trypsinogen activation (widely regarded as the key event of pancreatitis), and explore its mechanism, time course, and downstream consequences during pancreatic injury. CP was induced in mice by repeated episodes of acute pancreatitis (AP) based on caerulein hyperstimulation. ER stress leads to activation of unfolded protein response components that were measured in CP and AP. We show sustained up-regulation of unfolded protein response components ATF4, CHOP, GRP78, and XBP1 in CP. Overexpression of GRP78 and ATF4 in human CP confirmed the experimental findings. We used novel trypsinogen-7 knock-out mice (T(-/-)), which lack intra-acinar trypsinogen activation, to clarify the relationship of ER stress to intra-acinar trypsinogen activation in pancreatic injury. Comparable activation of ER stress was seen in wild type and T(-/-) mice. Induction of ER stress occurred through pathologic calcium signaling very early in the course of pancreatic injury. Our results establish that ER stress is chronically activated in CP and is induced early in pancreatic injury through pathologic calcium signaling independent of trypsinogen activation. ER stress may be an important pathogenic mechanism in pancreatitis that needs to be explored in future studies.

Acinar Cells - enzymology

Acinar Cells - metabolism

Activating Transcription Factor 4 - genetics

Activating Transcription Factor 4 - metabolism

Animals

Endoplasmic Reticulum Stress

Female

Heat-Shock Proteins - genetics

Heat-Shock Proteins - metabolism

Humans

Male

Mice

Pancreatitis, Chronic - enzymology

Pancreatitis, Chronic - genetics

Pancreatitis, Chronic - metabolism

Trypsinogen - genetics

Trypsinogen - metabolism

Unfolded Protein Response

Details

Title: Subtitle: Endoplasmic reticulum stress is chronically activated in chronic pancreatitis
Creators: Raghuwansh P Sah - University of Minnesota
Sushil K Garg - University of Minnesota
Ajay K Dixit - University of Minnesota
Vikas Dudeja - University of Minnesota
Rajinder K Dawra - University of Minnesota
Ashok K Saluja - University of Minnesota
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.289(40), pp.27551-27561
DOI: 10.1074/jbc.M113.528174
PMID: 25077966
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Grant note: R01 DK092145 / NIDDK NIH HHS DK093047 / NIDDK NIH HHS DK092145 / NIDDK NIH HHS R01 CA124723 / NCI NIH HHS R01 DK093047 / NIDDK NIH HHS R01 DK058694 / NIDDK NIH HHS DK058694 / NIDDK NIH HHS
Language: English
Date published: 10/03/2014
Academic Unit: Anatomy and Cell Biology; Surgery
Record Identifier: 9985244576202771

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