Inhibition of cathepsin B protects pancreatic acinar cells against apoptosis in early pancreatic trauma in rats

Abstract Premature trypsinogen activation is the early event of acute pancreatitis. Therefore, the studies on the processes of trypsinogen activation induced by compounds are important to understand mechanism underly acute pancreatitis under various conditions. Calcium overload in the early stage of acute pancreatitis was previously found to cause intracellular trypsinogen activation; however, treatment of acute pancreatitis using calcium channel blockers did not produced consistent results. Proteasome activity that could be inhibited by some calcium channel blocker has recently been reported to affect the development of acute pancreatitis; however, the associated mechanism were not fully understood. Here, the roles of nicardipine were investigated in trypsinogen activation in pancreatic acinar cells. The results showed that nicardipine could increase cathepsin B activity that caused trypsinogen activation, but higher concentration of nicardipine or prolonged treatment had an opposite effect. The effects of short time treatment of nicardipine at low concentration were studied here. Proteasome inhibition was observed under nicardipine treatment that contributed to the up-regulation in cytosolic calcium. Increased cytosolic calcium from ER induced by nicardipine resulted in the release and activation of cathepsin B. Meanwhile, calcium chelator inhibited cathepsin B as well as trypsinogen activation. Consistently, proteasome activator protected acinar cells from injury induced by nicardipine. Moreover, proteasome inhibition caused by nicardipine depended on CaMKII. In conclusion, CaMKII down-regulation/proteasome inhibition/cytosolic calcium up-regulation/cathepsin B activation/trypsinogen activation axis was present in pancreatic acinar cells injury under nicardipine treatment.

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Cathepsin B Activity Initiates Apoptosis via Digestive Protease Activation in Pancreatic Acinar Cells and Experimental Pancreatitis

Journal of Biological Chemistry ◽

10.1074/jbc.m116.718999 ◽

2016 ◽

Vol 291 (28) ◽

pp. 14717-14731 ◽

Cited By ~ 40

Author(s):

Matthias Sendler ◽

Sandrina Maertin ◽

Daniel John ◽

Maria Persike ◽

F. Ulrich Weiss ◽

...

Keyword(s):

Cathepsin B ◽

Acinar Cells ◽

Experimental Pancreatitis ◽

Pancreatic Acinar Cells ◽

Protease Activation

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Cathepsin B and D deficiency in the mouse pancreas induces impaired autophagy and chronic pancreatitis

Scientific Reports ◽

10.1038/s41598-021-85898-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hideaki Iwama ◽

Sally Mehanna ◽

Mai Imasaka ◽

Shinsuke Hashidume ◽

Hiroshi Nishiura ◽

...

Keyword(s):

Chronic Pancreatitis ◽

Cathepsin B ◽

Gene Knockout ◽

Cathepsin L ◽

Acinar Cells ◽

Pancreatic Acinar Cells ◽

Double Knockout ◽

Lysosomal Proteases ◽

Autophagic Activity

AbstractThe major lysosomal proteases, Cathepsin B (CTSB), Cathepsin D (CTSD) and Cathepsin L (CTSL), are implicated in autophagic activity. To investigate the role of each cathepsin in the exocrine pancreas, we generated mice in which the pancreas was specifically deficient in Ctsb, Ctsd and Ctsl. Each of these gene knockout (KO) and Ctsb;Ctsl and Ctsd;Ctsl double-knockout (DKO) mice were almost normal. However, we found cytoplasmic degeneration in the pancreatic acinar cells of Ctsb;Ctsd DKO mice, similar to autophagy related 5 (Atg5) KO mice. LC3 and p62 (autophagy markers) showed remarkable accumulation and the numbers of autophagosomes and autolysosomes were increased in the pancreatic acinar cells of Ctsb;Ctsd DKO mice. Moreover, these Ctsb;Ctsd DKO mice also developed chronic pancreatitis (CP). Thus, we conclude that both Ctsb and Ctsd deficiency caused impaired autophagy in the pancreatic acinar cells, and induced CP in mice.

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