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TRPV4 channel opening mediates pressure-induced pancreatitis initiated by Piezo1 activation
Sandip M. Swain, … , Steven R. Vigna, Rodger A. Liddle
Sandip M. Swain, … , Steven R. Vigna, Rodger A. Liddle
Published January 30, 2020
Citation Information: J Clin Invest. 2020;130(5):2527-2541. https://doi.org/10.1172/JCI134111.
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Research Article Gastroenterology Article has an altmetric score of 12

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

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Abstract

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.

Authors

Sandip M. Swain, Joelle M.-J. Romac, Rafiq A. Shahid, Stephen J. Pandol, Wolfgang Liedtke, Steven R. Vigna, Rodger A. Liddle

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Figure 4

Fluid shear stress induces mitochondrial depolarization and trypsinogen activation in pancreatic acini.

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Fluid shear stress induces mitochondrial depolarization and trypsinogen ...
(A) Pancreatic acini were subjected to fluid shear force of 12 dyne/cm2, and TMRE dye fluorescence intensity of pancreatic acinar cells from WT and Piezo1aci-KO mice were measured over 15 minutes. The duration of shear stress for 30 seconds is marked by the orange bar. FD represents the decrease in TMRE fluorescence over time, and F0 represents the base line TMRE intensity before fluid shear stress. (B) The mean average decrease in fluorescence intensity of TMRE over 15 minutes is shown. Flow is the lowest TMRE fluorescent intensity after fluid shear stress during imaging. The total number of acinar cells examined were as follows: control (without fluid shear stress) = 56; fluid shear stress on WT acini = 50; and fluid shear stress on Piezo1aci-KO acini = 91 and WT acini = 67. n = 3 independent experiments. (C) Traces represent live-cell trypsin activity upon fluid shear stress of 12 dyne/cm2 for 30 seconds in acini from WT or Piezo1aci-KO mice. n = 3 experiments. (D) Peak fluorescence intensity of BZiPAR over 50 minutes from 3 experiments; total number of acinar cells were as follows: WT = 28 and Piezo1aci-KO = 36. Data are shown as the mean ± SEM. ****P ≤ 0.0001. Statistical analyses were performed using Student’s t test (B) and 1-way ANOVA with Tukey’s multiple comparison (D).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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