An Orally Active TRPV4 Channel Blocker Prevents and Resolves Pulmonary Edema Induced by Heart Failure

Thorneloe, Kevin S.; Cheung, Mui; Bao, Weike; Alsaid, Hasan; Lenhard, Stephen C.; Jian, Ming; Costell, Melissa H.; Maniscalco-Hauk, Kristeen; Krawiec, John A.; Olzinski, Alan R.; Gordon, Earl; Lozinskaya, Irina M.; Elefante, Lou; Qin, Pu; Matasic, Daniel S.; James, Chris; Tunstead, James; Donovan, Brian T.; Kallal, Lorena A.; Waszkiewicz, Anna; Vaidya, Kalindi; Davenport, Elizabeth A.; Larkin, J.; Burgert, Mark; Casillas, Linda; Marquis, Robert W.; Ye, Guosen; Eidam, Hilary S.; Goodman, Krista B.; Toomey, John R.; Roethke, Theresa J.; Jucker, Beat M.; Schnackenberg, Christine G.; Townsley, Mary I.; Lepore, John J.; Willette, Robert N.

doi:10.1126/scitranslmed.3004276

Cited by 294 publications

(365 citation statements)

References 43 publications

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“…The recent discovery of its localization to cilia suggested its potential role in the pathophysiology of glaucoma in the TM of eyes (4,6,7). TRPV4 has been well recognized to be a mechanosensor in kidney epithelial cells, as well as in a number of other fluidregulating cell types (32,37,38,40). Here we show that OCRL interacts with TRPV4.…”

Section: Discussionmentioning

confidence: 54%

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Primary cilia signaling mediates intraocular pressure sensation

Luo

Conwell

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

119

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Lowe syndrome is a rare X-linked congenital disease that presents with congenital cataracts and glaucoma, as well as renal and cerebral dysfunction. OCRL, an inositol polyphosphate 5-phosphatase, is mutated in Lowe syndrome. We previously showed that OCRL is involved in vesicular trafficking to the primary cilium. Primary cilia are sensory organelles on the surface of eukaryotic cells that mediate mechanotransduction in the kidney, brain, and bone. However, their potential role in the trabecular meshwork (TM) in the eye, which regulates intraocular pressure, is unknown. Here, we show that TM cells, which are defective in glaucoma, have primary cilia that are critical for response to pressure changes. Primary cilia in TM cells shorten in response to fluid flow and elevated hydrostatic pressure, and promote increased transcription of TNF-α, TGF-β, and GLI1 genes. Furthermore, OCRL is found to be required for primary cilia to respond to pressure stimulation. The interaction of OCRL with transient receptor potential vanilloid 4 (TRPV4), a ciliary mechanosensory channel, suggests that OCRL may act through regulation of this channel. A novel disease-causing OCRL allele prevents TRPV4-mediated calcium signaling. In addition, TRPV4 agonist GSK 1016790A treatment reduced intraocular pressure in mice; TRPV4 knockout animals exhibited elevated intraocular pressure and shortened cilia. Thus, mechanotransduction by primary cilia in TM cells is implicated in how the eye senses pressure changes and highlights OCRL and TRPV4 as attractive therapeutic targets for the treatment of glaucoma. Implications of OCRL and TRPV4 in primary cilia function may also shed light on mechanosensation in other organ systems.

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Section: Discussionmentioning

confidence: 54%

“…TRPV4 is a mechanosensitive calcium-permeable cation channel that localizes to cilia, where it functions in osmotic regulation (32,(37)(38)(39). TRPV4 dysregulation has been implicated in diseases with fluid overload, such as hydrocephalus and heart failure (32,40). Therefore, we investigated if OCRL and TRPV4 may play a role in TM cilia.…”

Section: Resultsmentioning

confidence: 99%

Primary cilia signaling mediates intraocular pressure sensation

Luo

Conwell

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

119

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“…TRPV4 has been implicated recently in the differentiation of chondrocytes, osteoclasts, and cardiac myofibroblasts via Ca 2+ influx (29)(30)(31). It has been reported that TRPV4 initiates the acute calcium-dependent vascular permeability in pulmonary edema that develops upon ventilator-induced lung injury or by elevated pulmonary venous pressure associated with heart failure in mice (32,33). However, TRPV4 has not been previously shown to be involved in lung myofibroblast differentiation or fibrosis, and the molecular mechanism of its involvement in this process has not been determined.…”

Section: Introductionmentioning

confidence: 99%

TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice

et al. 2014

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“…The team already has used the lung-on-a-chip model in proofof-concept studies to test potential pulmonary edema therapeutic candidates including GlaxoSmithKline plc's GSK2193874, an inhibitor of transient receptor potential vanilloid 4 (TRPV4; VRL2), 3 and wants to expand the use of the chip to model multiple lung diseases.…”

Section: By Lauren Martz Staff Writermentioning

confidence: 99%

“…in a paper published in Science Translational Medicine, 3 Kevin thorneloe and colleagues used small molecule screening and chemical optimization to develop GsK2193874. thorneloe is a senior scientific investigator at GsK.…”

Section: By Lauren Martz Staff Writermentioning

confidence: 99%

Pulmonary edema on a chip

Martz¹

2012

Science-Business eXchange

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1 through the fluid microchannel and monitored fluid leak across the endothelium and into the alveolar air space.IL-2 induced a fluid leak that continued for four days and decreased air volume compared with no treatment. The administration of both IL-2 and human blood plasma proteins caused fluid leak and fibrin clot formation that occur during the disease.The application of mechanical strains to mimic breathing further compromised the barrier between the endothelium and alveolar epithelium and enhanced the leakage caused by IL-2. In contrast, mechanical strain in the absence of IL-2 did not alter barrier integrity.These findings suggest breathing may exacerbate pulmonary edema and that artificial ventilation may be counterproductive in patients with pulmonary edema.Finally, the Wyss group used the model to test potential therapeutics. Application of GSK2193874 or angiopoietin 1 (ANG1; ANGPT1), an antagonist of the edema-inducing ANG2 (ANGPT2), inhibited IL-2-induced pulmonary edema.Silence Therapeutics plc has Atu111, a small interfering RNA therapeutic targeting ANG2, in preclinical testing to treat acute lung injury.The data were published in Science Translational Medicine. The authors included researchers from GSK and Seoul National University. Breathing easyThe Boston team hopes to use the organ-on-a-chip technology to decrease the number of or replace many types of preclinical studies."Our next step is to explore what additional data might be required to convince pharmaceutical companies and the FDA that data produced by an on-chip model of human pulmonary edema could be used in place of results from an animal model of this condition to advance a drug toward testing in humans, " Ingber told SciBX.He said that unlike other in vitro models, the lung on a chip allows the study of organ-level functions. As for in vivo models, he said, "the chips should be faster and cheaper than animals. "Wolfgang Kübler, associate professor of surgery and physiology at the University of Toronto, was less bullish on the potential for taking animal studies out of the equation. "The model does not replicate animal experiments and the ability to study an entire organ or body," he said. "The litmus test still has to be in vivo, but this is certainly a good screening tool that may give a better indication of therapeutic success than simple cell cultures. " Ingber said the model should be extendable to other lung conditions. For example, he said, the device could monitor the effects of aerosol-based toxins or aerosolized nanoparticles, aerosol-based drug delivery, smoke or chemical inhalation injury, radiation injury, fibrosis, pneumonias and metastasis. Pulmonary edema on a chip By Lauren Martz, Staff WriterResearchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University have described the first disease model to emerge from the institute's organ-on-a-chip microfluidic device technology. 1,2 The model of pulmonary edema could be better than culture models at predicting whether therapeutics will translate...

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An Orally Active TRPV4 Channel Blocker Prevents and Resolves Pulmonary Edema Induced by Heart Failure

Cited by 294 publications

References 43 publications

Primary cilia signaling mediates intraocular pressure sensation

Primary cilia signaling mediates intraocular pressure sensation

TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice

Pulmonary edema on a chip

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