Skip to main content

TRPV4 channel opening mediates pressure-induced pancreatitis initiated by Piezo1 activation.

Publication ,  Journal Article
Swain, SM; Romac, JM-J; Shahid, RA; Pandol, SJ; Liedtke, W; Vigna, SR; Liddle, RA
Published in: J Clin Invest
May 1, 2020

Elevated pressure in the pancreatic gland is the central cause of pancreatitis following abdominal trauma, surgery, endoscopic retrograde cholangiopancreatography, and gallstones. In the pancreas, excessive intracellular calcium causes mitochondrial dysfunction, premature zymogen activation, and necrosis, ultimately leading to pancreatitis. Although stimulation of the mechanically activated, calcium-permeable ion channel Piezo1 in the pancreatic acinar cell is the initial step in pressure-induced pancreatitis, activation of Piezo1 produces only transient elevation in intracellular calcium that is insufficient to cause pancreatitis. Therefore, how pressure produces a prolonged calcium elevation necessary to induce pancreatitis is unknown. We demonstrate that Piezo1 activation in pancreatic acinar cells caused a prolonged elevation in intracellular calcium levels, mitochondrial depolarization, intracellular trypsin activation, and cell death. Notably, these effects were dependent on the degree and duration of force applied to the cell. Low or transient force was insufficient to activate these pathological changes, whereas higher and prolonged application of force triggered sustained elevation in intracellular calcium, leading to enzyme activation and cell death. All of these pathological events were rescued in acinar cells treated with a Piezo1 antagonist and in acinar cells from mice with genetic deletion of Piezo1. We discovered that Piezo1 stimulation triggered transient receptor potential vanilloid subfamily 4 (TRPV4) channel opening, which was responsible for the sustained elevation in intracellular calcium that caused intracellular organelle dysfunction. Moreover, TRPV4 gene-KO mice were protected from Piezo1 agonist- and pressure-induced pancreatitis. These studies unveil a calcium signaling pathway in which a Piezo1-induced TRPV4 channel opening causes pancreatitis.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

May 1, 2020

Volume

130

Issue

5

Start / End Page

2527 / 2541

Location

United States

Related Subject Headings

  • Thiadiazoles
  • TRPV Cation Channels
  • Pyrazines
  • Pressure
  • Pancreatitis
  • Pancreas
  • Models, Biological
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Swain, S. M., Romac, J.-J., Shahid, R. A., Pandol, S. J., Liedtke, W., Vigna, S. R., & Liddle, R. A. (2020). TRPV4 channel opening mediates pressure-induced pancreatitis initiated by Piezo1 activation. J Clin Invest, 130(5), 2527–2541. https://doi.org/10.1172/JCI134111
Swain, Sandip M., Joelle M-J Romac, Rafiq A. Shahid, Stephen J. Pandol, Wolfgang Liedtke, Steven R. Vigna, and Rodger A. Liddle. “TRPV4 channel opening mediates pressure-induced pancreatitis initiated by Piezo1 activation.J Clin Invest 130, no. 5 (May 1, 2020): 2527–41. https://doi.org/10.1172/JCI134111.
Swain SM, Romac JM-J, Shahid RA, Pandol SJ, Liedtke W, Vigna SR, et al. TRPV4 channel opening mediates pressure-induced pancreatitis initiated by Piezo1 activation. J Clin Invest. 2020 May 1;130(5):2527–41.
Swain, Sandip M., et al. “TRPV4 channel opening mediates pressure-induced pancreatitis initiated by Piezo1 activation.J Clin Invest, vol. 130, no. 5, May 2020, pp. 2527–41. Pubmed, doi:10.1172/JCI134111.
Swain SM, Romac JM-J, Shahid RA, Pandol SJ, Liedtke W, Vigna SR, Liddle RA. TRPV4 channel opening mediates pressure-induced pancreatitis initiated by Piezo1 activation. J Clin Invest. 2020 May 1;130(5):2527–2541.

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

May 1, 2020

Volume

130

Issue

5

Start / End Page

2527 / 2541

Location

United States

Related Subject Headings

  • Thiadiazoles
  • TRPV Cation Channels
  • Pyrazines
  • Pressure
  • Pancreatitis
  • Pancreas
  • Models, Biological
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice