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      Piezo2 downregulation via the Cre-lox system affects aqueous humor dynamics in mice

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          Abstract

          Purpose

          Proper aqueous humor (AH) dynamics is crucial for maintaining the intraocular pressure (IOP) in the eye. This study aims to investigate the function of Piezo2, a newly discovered mechanosensitive ion channel, in regulating AH dynamics.

          Methods

          Immunohistochemistry (IHC) analysis and western blotting were performed to detect Piezo2 expression. The Cre-lox system was applied to create a conditional knockout model of Piezo2. IOP and aqueous humor outflow facility in live animals were recorded with a Tonometer and a syringe-pump system for up to 2 weeks.

          Results

          We first detected Piezo2 with robust expression in the human trabecular meshwork (TM), Schlemm’s canal (SC), the ciliary body’s epithelium, and ciliary muscle. In addition, we found Piezo2 in human retinal ganglion cells (RGCs) and astrocytes in the optic nerve head (ONH). Through the Cre-lox system, Piezo2 can be successfully downregulated in mouse iridocorneal angle tissues. However, Piezo2 downregulation cannot significantly influence the IOP and outflow facility through the conventional pathway. Instead, we observed an effect of downregulated Piezo2 on decreasing the intercept in the flow rate versus pressure plot. According to the Goldmann equation, Piezo2 may function in regulating unconventional outflow, AH production, and episcleral venous pressure.

          Conclusions

          These findings, for the first time, demonstrate that Piezo2 acts as an essential mechanosensor in maintaining the proper aqueous humor dynamics in the eye.

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          Most cited references42

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          The pathophysiology and treatment of glaucoma: a review.

          Robert N. Weinreb, Tin Aung, Felipe Medeiros (2014)
          Glaucoma is a worldwide leading cause of irreversible vision loss. Because it may be asymptomatic until a relatively late stage, diagnosis is frequently delayed. A general understanding of the disease pathophysiology, diagnosis, and treatment may assist primary care physicians in referring high-risk patients for comprehensive ophthalmologic examination and in more actively participating in the care of patients affected by this condition. To describe current evidence regarding the pathophysiology and treatment of open-angle glaucoma and angle-closure glaucoma. A literature search was conducted using MEDLINE, the Cochrane Library, and manuscript references for studies published in English between January 2000 and September 2013 on the topics open-angle glaucoma and angle-closure glaucoma. From the 4334 abstracts screened, 210 articles were selected that contained information on pathophysiology and treatment with relevance to primary care physicians. The glaucomas are a group of progressive optic neuropathies characterized by degeneration of retinal ganglion cells and resulting changes in the optic nerve head. Loss of ganglion cells is related to the level of intraocular pressure, but other factors may also play a role. Reduction of intraocular pressure is the only proven method to treat the disease. Although treatment is usually initiated with ocular hypotensive drops, laser trabeculoplasty and surgery may also be used to slow disease progression. Primary care physicians can play an important role in the diagnosis of glaucoma by referring patients with positive family history or with suspicious optic nerve head findings for complete ophthalmologic examination. They can improve treatment outcomes by reinforcing the importance of medication adherence and persistence and by recognizing adverse reactions from glaucoma medications and surgeries.
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            The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration.The AGIS Investigators.

            (2000)
            To investigate the association between control of intraocular pressure after surgical intervention for glaucoma and visual field deterioration. In the Advanced Glaucoma Intervention Study, eyes were randomly assigned to one of two sequences of glaucoma surgery, one beginning with argon laser trabeculoplasty and the other trabeculectomy. In the present article we examine the relationship between intraocular pressure and progression of visual field damage over 6 or more years of follow-up. In the first analysis, designated Predictive Analysis, we categorize 738 eyes into three groups based on intraocular pressure determinations over the first three 6-month follow-up visits. In the second analysis, designated Associative Analysis, we categorize 586 eyes into four groups based on the percent of 6-month visits over the first 6 follow-up years in which eyes presented with intraocular pressure less than 18 mm Hg. The outcome measure in both analyses is change from baseline in follow-up visual field defect score (range, 0 to 20 units). In the Predictive Analysis, eyes with early average intraocular pressure greater than 17.5 mm Hg had an estimated worsening during subsequent follow-up that was 1 unit of visual field defect score greater than eyes with average intraocular pressure less than 14 mm Hg (P =.002). This amount of worsening was greater at 7 years (1.89 units; P <.001) than at 2 years (0.64 units; P =.071). In the Associative Analysis, eyes with 100% of visits with intraocular pressure less than 18 mm Hg over 6 years had mean changes from baseline in visual field defect score close to zero during follow-up, whereas eyes with less than 50% of visits with intraocular pressure less than 18 mm Hg had an estimated worsening over follow-up of 0.63 units of visual field defect score (P =.083). This amount of worsening was greater at 7 years (1.93 units; P <.001) than at 2 years (0.25 units; P =.572). In both analyses low intraocular pressure is associated with reduced progression of visual field defect, supporting evidence from earlier studies of a protective role for low intraocular pressure in visual field deterioration.
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              Mechanically Activated Ion Channels.

              Sanjeev S Ranade, Ruhma Syeda, Ardem Patapoutian (2015)
              Mechanotransduction, the conversion of physical forces into biochemical signals, is essential for various physiological processes such as the conscious sensations of touch and hearing, and the unconscious sensation of blood flow. Mechanically activated (MA) ion channels have been proposed as sensors of physical force, but the identity of these channels and an understanding of how mechanical force is transduced has remained elusive. A number of recent studies on previously known ion channels along with the identification of novel MA ion channels have greatly transformed our understanding of touch and hearing in both vertebrates and invertebrates. Here, we present an updated review of eukaryotic ion channel families that have been implicated in mechanotransduction processes and evaluate the qualifications of the candidate genes according to specified criteria. We then discuss the proposed gating models for MA ion channels and highlight recent structural studies of mechanosensitive potassium channels.
              Article 0 comments Cited 215 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mol Vis
                Journal ID (iso-abbrev): Mol Vis
                Journal ID (publisher-id): MV
                Title: Molecular Vision
                Publisher: Molecular Vision
                ISSN (Electronic): 1090-0535
                Publication date Collection: 2021
                Publication date (Electronic): 20 May 2021
                Volume: 27
                Pages: 354-364
                Affiliations
                [1 ]Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, China
                [2 ]Beijing Institute of Ophthalmology, Beijing Tongren Hospital Eye Center, Beijing, China
                [3 ]Qingdao Haier Biotech Co. Ltd, Qingdao, China
                [4 ]Institute of Innovative Drugs, Qingdao University, Qingdao, China
                [5 ]Advanced Innovation Center for Big Data-Based Precision Medicine, Beijing University of Aeronautics and Astronautics-Capital Medical University, Beijing, China
                Author notes
                Correspondence to: Wei Zhu, Department of Pharmacology, Qingdao University, 38 Dengzhou Rd., Qingdao, Shandong 266021, China; Phone: +86(0532)82991202; FAX: +86(0532)83801449; email: wzhu@ 123456qdu.edu.cn
                Article
                Publisher ID: 28 Publisher-manuscript ID: 2020MOLVIS0161
                PMC ID: 8219506
                PubMed ID: 34220183
                SO-VID: 3c1ac680-be43-4150-863e-b7e026585689
                Copyright © Copyright © 2021 Molecular Vision.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited, used for non-commercial purposes, and is not altered or transformed.

                History
                Date received : 01 July 2020
                Date accepted : 18 May 2021
                Categories
                Subject: Research Article
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                ScienceOpen disciplines: Vision sciences
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                ScienceOpen disciplines: Vision sciences

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