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

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

doi:10.1172/jci134111

Cited by 129 publications

(140 citation statements)

References 90 publications

(138 reference statements)

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“…The sensitivity of flow-induced signals to GsMTx4 and Piezo1 knockdown identifies Piezo1 as the principal transducer of these responses. The fraction (~15%) of the flow-induced signal that was mediated by TRPV4 is in line with reports of TRPV4dependent shear transduction in SMCs and endothelia (67)(68)(69)(70). It is possible that the TRPV4 component might increase at shear stresses induced by larger pressure gradients (67-69).…”

Section: Discussionsupporting

confidence: 89%

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Mechanotransduction and dynamic outflow regulation in trabecular meshwork requires Piezo1 channels

Yarishkin

Phuong

Baumann

et al. 2020

Preprint

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AbstractMechanosensitivity of the trabecular meshwork (TM) is a key determinant of intraocular pressure (IOP) yet our understanding of the molecular mechanisms that subserve it remains in its infancy. Here, we show that mechanosensitive Piezo1 channels modulate the TM pressure response via calcium signaling and dynamics of the conventional outflow pathway. Pressure steps evoked fast, inactivating cation currents and calcium signals that were inhibited by Ruthenium Red, GsMTx4 and Piezo1 shRNA. Piezo1 expression was confirmed by transcript and protein analysis, and by visualizing Yoda1-mediated currents and [Ca2+]i elevations in primary human TM cells. Piezo1 activation was obligatory for transduction of physiological shear stress and was coupled to reorganization of F-actin cytoskeleton and focal adhesions. The importance of Piezo1 channels as pressure sensors was shown by the GsMTx4 -dependence of the pressure-evoked current and conventional outflow function. We also demonstrate that Piezo1 collaborates with the stretch-activated TRPV4 channel, which mediated slow, delayed currents to pressure steps. Collectively, these results suggest that TM mechanosensitivity utilizes kinetically, regulatory and functionally distinct pressure transducers to inform the cells about force-sensing contexts. Piezo1-dependent control of shear flow sensing, calcium homeostasis, cytoskeletal dynamics and pressure-dependent outflow suggests a novel potential therapeutic target for treating glaucoma.Significance StatementTrabecular meshwork (TM) is a highly mechanosensitive tissue in the eye that regulates intraocular pressure through the control of aqueous humor drainage. Its dysfunction underlies the progression of glaucoma but neither the mechanisms through which TM cells sense pressure nor their role in aqueous humor outflow are understood at the molecular level. We identified the Piezo1 channel as a key TM transducer of tensile stretch, shear flow and pressure. Its activation resulted in intracellular signals that altered organization of the cytoskeleton and cell-extracellular matrix contacts, and modulated the trabecular component of aqueous outflow whereas another channel, TRPV4, mediated a delayed mechanoresponse. These findings provide a new mechanistic framework for trabecular mechanotransduction and its role in the regulation of fast fluctuations in ocular pressure, as well as chronic remodeling of TM architecture that epitomizes glaucoma.

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Section: Discussionsupporting

confidence: 89%

“…agonists and pressure (15) channel activation (15,89). Its manifestation in the absence of the fast component and resistance to GsMTx4 argue against Piezo1-TRPV4 coupling seen in pancreatic acinar cells (70).…”

Section: Discussionmentioning

confidence: 99%

Mechanotransduction and dynamic outflow regulation in trabecular meshwork requires Piezo1 channels

Yarishkin

Phuong

Baumann

et al. 2020

Preprint

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“…Our findings suggest that Piezo1 or TRPV4 alone is not sufficient to transduce mechanical force into pathological events. We have previously demonstrated that coupling of Piezo1 with TRPV4 is responsible for the effects of high pressure in pancreatic acinar cells (28). If functional coupling between Piezo1-TRPV4 is a generalized process in which TRPV4 translates the mechanical force sensed by Piezo1 into pathological events, then other organ systems like urinary bladder and bone tissue where Piezo1and TRPV4 are coexpressed (21,(54)(55)(56)(57), may also be amenable to targeting Piezo1 or TRPV4 to prevent adverse effects of pressure or shear stress.…”

Section: Discussionmentioning

confidence: 99%

“…We recently observed that stimulation of Piezo1 in pancreatic acinar cells is responsible for pressure-induced pancreatitis (27) and is linked to TRPV4 (28).…”

Section: Introductionmentioning

confidence: 99%

“…Though shear stress and cell swelling activate TRPV4 channel activity, TRPV4 senses mechanical force indirectly. During shear stress, TRPV4 is activated by 5,6 -EET, which is an endogenous ligand derived from arachidonic acid through the activation of PLA2(26,28). Recently, we discovered that high pressure-induced Piezo1 activation caused the stimulation of PLA2 and subsequent opening of TRPV4 in pancreatic acinar cells(28).…”

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confidence: 99%

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Shear stress-induced pathological changes in endothelial cells occur through Piezo1 activation of TRPV4

Swain

Liddle

2020

Preprint

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AbstractAlthough the ion channels Piezo1 and TRPV4 have been implicated in high venous pressure- and fluid shear stress-induced vascular hyperpermeability, they have been described as working independently. Moreover, the mechanism by which Piezo1 and TRPV4 channels in endothelial cells execute the same function is poorly understood. Here we demonstrate that Piezo1 regulates TRPV4 channel activation in endothelial cells and that Piezo1-mediated TRPV4 channel opening is a function of the strength and duration of fluid shear stress. Application of the Piezo1 antagonist, GsMTx4, completely blocked the elevation in intracellular calcium ([Ca2+]i) induced by both fluid shear stress and the Piezo1 agonist, Yoda1. High and prolonged shear stress caused sustained [Ca2+]i elevation which required TRPV4 opening and was responsible for fluid shear stress- and Piezo1-mediated disruption of adherens junctions and actin remodeling. We found that Piezo1’s effects were mediated by phospholipase A2 activation. Blockade of TRPV4 channels with the selective TRPV4 blocker, HC067047, prevented the loss of endothelial cell integrity and actin disruption induced by Yoda1 or shear stress and prevented Piezo1-induced monocyte adhesion to endothelial cell monolayers. These findings demonstrate that Piezo1 activation by fluid shear stress initiates a calcium signal that causes TRPV4 opening which in turn is responsible for the sustained phase calcium elevation that triggers pathological events in endothelial cells.

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The Role of Neurogenic Inflammation in Pancreatitis

Nader

Saloman

2023

The Pancreas

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

Cited by 129 publications

References 90 publications

Mechanotransduction and dynamic outflow regulation in trabecular meshwork requires Piezo1 channels

Mechanotransduction and dynamic outflow regulation in trabecular meshwork requires Piezo1 channels

Shear stress-induced pathological changes in endothelial cells occur through Piezo1 activation of TRPV4

The Role of Neurogenic Inflammation in Pancreatitis

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