Pressure‐sensing Piezo1: the eyes have it

Intraocular pressure is controlled by the mechanosensitive trabecular meshwork (TM) tissue which regulates the flow of aqueous humour in the anterior chamber of the eye. Sustained increases in intraocular pressure result from exfoliation of cell debris and TM remodelling which, through contractile pressure-sensing cells of the juxtacanalicular and corneoscleral regions, regulate the flow of aqueous humour into Schlemm's canal. Resting intraocular pressures (7–15 mmHg) are maintained for the normal growth and shape of the eye through the dynamic outflow of aqueous humour. By virtue of their mechanosensitivity, TM cells have the ability to respond to changes in intraocular pressure and adjust the outflow of aqueous humour to maintain pressures in a normal range. Although TM cells express ion channels such as TRPV4 and TREK1 that are activated by changes in intraocular pressure, what initiates the response to abrupt pressure changes and how TM cells quickly react to control the outflow of aqueous humour is not clear (Ryskamp et al. 2016; Yarishkin et al. 2018). Yarishkin, Phuong et al., in this issue of The Journal of Physiology, demonstrate that TM cells express the mechanosensitive ion channel Piezo1, which acts as a direct pressure sensor and regulates intraocular pressure by controlling the outflow of aqueous humour (Yarishkin et al. 2021). Piezo1 is a fast-inactivating channel compared to other mechanically activated non-selective cation channels. In this study, brief application of pressure on cells isolated from the juxtacanalicular and corneoscleral regions produced an inward current in 96% of cells; 72% of cells exhibited a fast-activating current alone, while 14% of cells showed both fast and slow components, suggesting co-expression. The fast-activating current was largely mediated by Piezo1 while the slow, sustained current required the activation of TRPV4. Physiological shear stress increased intracellular calcium levels, which were inhibited by the Piezo1 antagonist GsMTx4; but this change was largely unaffected by the TRPV4 antagonist HC067047. GsMTx4 also inhibited the sequential steps in pressure-induced outflow. Therefore, although both Piezo1 and TRPV4 are expressed in TM cells, it appears that Piezo1 is the principal transducer of rapid pressure changes in cells of the juxtacanalicular and corneoscleral regions and, in healthy eyes, may maintain normal intraocular pressure. It was recently reported that prolonged shear stress in pancreatic acini activates Piezo1 channels and Piezo1-mediated calcium influx caused the opening of TRPV4 channels through calcium-dependent phospholipase A2 (Swain et al. 2020). In acinar cells, Piezo1-stimulated TRPV4 activation led to high intracellular calcium concentrations and deleterious consequences. Thus, under pathological conditions, Piezo1 activation was linked to TRPV4. It will be interesting to determine if similar coupling occurs in TM cells that might result in disease such as glaucoma. In glaucoma, resistance to flow of aqueous humour is primarily due to accumulation and deposition of extracellular matrix (ECM) proteins and increased TM cell stiffness (Last et al. 2011). In the current study, pharmacological activation of Piezo1 with Yoda1 or mechanical shear stress led to cytoskeletal and cell-ECM remodelling. Previously the authors had reported that selective TRPV4 activation led to actin polymerization in TMs, suggesting that intracellular calcium elevation might be responsible for actin polymerization (Ryskamp et al. 2016). Therefore, prolonged Piezo1 and/or TRPV4 activation may produce similar pathological results, in which case, in the eye, blocking Piezo1 or TRPV4 could be a possible treatment for glaucoma. If Piezo1 and TRPV4 are co-expressed in the same cell, then conditions that activate Piezo1 such as prolonged pressure or shear stress would lead to TRPV4 activation and pathological changes, i.e. actin polymerization. Thus, it should also be possible to target TM cells with either a Piezo1 or TRPV4 inhibitor to prevent adverse effects of pressure or shear stress. The current study was conducted by applying transient forces to understand the physiology of Piezo1 channel kinetics. Dissecting the interactions between Piezo1 and TRPV4 will be best accomplished using models with genetic deletion of Piezo1 or Trpv4 specifically in TM cells. These models could also be used to determine the role of Piezo1 and TRPV4 in pathological conditions such as glaucoma. However, before targeting Piezo1 pathways to treat glaucoma, we need to understand the role of Piezo1 in glaucoma-associated ECM deposition. Two possibilities may underlie the involvement of Piezo1 in the etiopathogenesis of outflow obstruction of aqueous humour. Although increased ECM deposition in the juxtacanalicular region is well described in glaucoma, it is not known what comes first. Does increased intraocular pressure or flow cause prolonged Piezo1/TRPV4 activation in TM cells leading to ECM deposition? Or does a primary defect in the TM complex lead to ECM deposition which then obstructs aqueous outflow, resulting in increased intraocular pressure? These questions open the door for insightful future experiments to determine the effects of: (1) TM cell-specific Piezo1 deletion on the eye anatomy of mice with glaucoma, (2) changes in Piezo1-mediated downstream genes responsible for the progression of glaucoma, and (3) other factors known to be associated with glaucoma such as oxidative stress, infection, age and genetic factors on Piezo1 expression and regulation in TM cells. It remains to be seen how sustained intraocular pressure elevation in some types of glaucoma affects the Piezo1 pathway. Over 80 million people are affected by glaucoma worldwide, and over 4 million people have lost their vision. If Piezo1 is responsible for glaucoma then a strategy to target Piezo1 could offer a possible treatment. None. Both authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. This work was supported by NIH grants R01 120555, 125308, and 124474 and the Department of Veterans Affairs grant BX002230.