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Wei Zhu, Mohammad Reza Bahrani Fard, C Ross Ethier, KeWei Wang; Mechanosensitive Piezo1 influences aqueous humor outflow dynamics in mice. Invest. Ophthalmol. Vis. Sci. 2020;61(7):3459.
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© ARVO (1962-2015); The Authors (2016-present)
The trabecular meshwork (TM) is mechanosensitive. We previously identified robust expression of Piezo1, a very sensitive mechanosensor, in the TM. The goal of this study was to investigate the function of Piezo1 in influencing aqueous humor outflow.
Whole-cell patch clamp recordings were performed in mouse primary TM cells at passages 3-6 as cells were mechanically indented. Measurements were made under control conditions, or after cells were treated with a selective antagonist for Piezo1 (GsMTx4) or a specific agonist for Piezo1 (Yoda1). To determine the influence of Piezo1 on outflow facility, paired enucleated 3 month old wild-type C57BL/6J mouse eyes were perfused (iPerfusion) using a standard protocol: stabilization at 8 mmHg for 45 min followed by perfusion at eight sequential pressure steps of 4.5, 6, 7.5, 9, 10.5, 12, 13.5, 15, and 16.5 mmHg. One eye received either 10 mM GsMTx4 in DBG solution (1×DPBS with 5.5 mM D-glucose) or 20 μM Yoda1 in DBG, while the contralateral eye received DBG alone (control).
Mechanical stimulation (indentation) of mouse TM cells caused currents with fast activation and inactivation kinetics. Treatment with 2.5 mM GsMTx-4 resulted in a significant (59.6 ± 7.1%, p=0.0046, n=7) decrease in the current amplitude, while 10 μM Yoda1 caused a significant 2.2-fold increase of Piezo1 current amplitude (-641.0 ± 200.6 vs. -292.7 ± 44.3 pA, p=5.5E-4, n=13). Inhibition of Piezo1 by GsMTx4 decreased outflow facility by 55.1% vs. control (3.1 ± 1.1 nl/min/mmHg vs. 6.9 ± 1.1 nl/min/mmHg, p=0.03, n=7). No significant effect of Yoda1 on outflow facility was observed (4.6 ± 4.0 nl/min/mmHg vs. 3.8 ± 1.2 nl/min/mmHg, p=0.61, n=9).
The Piezo1 mechanosensitive channel is functional in TM cells, responding to mechanical stimulation and affecting outflow facility. These data suggest it is important in aqueous humor outflow dynamics.
This is a 2020 ARVO Annual Meeting abstract.
Figure 1: Effect of the Piezo1 inhibitor, GsMTx4, on outflow facility in post mortem wild-type C57BL/6 mouse eyes. Facility of treated eyes is plotted vs contralateral control eyes. Points below the unity line (blue) indicate a reduction in facility due to GsMTx4. Red line: regression fit to data; red shading: 95% confidence interval to fit. Shaded ellipses surrounding individual points show confidence intervals (Sherwood JM, et al. PLoS One, 2016).
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