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

Research output: Contribution to journalArticle

40 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)27551-27561
Number of pages11
JournalJournal of Biological Chemistry
Volume289
Issue number40
DOIs
StatePublished - Oct 3 2014

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Endoplasmic Reticulum Stress
Chronic Pancreatitis
Trypsinogen
Chemical activation
Pancreatitis
Unfolded Protein Response
Calcium Signaling
Wounds and Injuries
Endoplasmic Reticulum
Calcium
Ceruletide
Acinar Cells
Knockout Mice
Proteins
Chronic Disease
Up-Regulation

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Endoplasmic reticulum stress is chronically activated in chronic pancreatitis. / Sah, Raghuwansh P.; Garg, Sushil K.; Dixit, Ajay K.; Dudeja, Vikas; Dawra, Rajinder K.; Saluja, Ashok K.

In: Journal of Biological Chemistry, Vol. 289, No. 40, 03.10.2014, p. 27551-27561.

Research output: Contribution to journalArticle

Sah, Raghuwansh P. ; Garg, Sushil K. ; Dixit, Ajay K. ; Dudeja, Vikas ; Dawra, Rajinder K. ; Saluja, Ashok K. / Endoplasmic reticulum stress is chronically activated in chronic pancreatitis. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 40. pp. 27551-27561.
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