TRPA1 mediates damage of the retina induced by ischemia and reperfusion in mice

Daniel Souza Monteiro De Araújo,Gianluca Mattei,Romina Nassini,Francesco De Logu,Lorenzo Landini,Alberto Magi,Karin Da Costa Calaza,Chiara Adembri,Pierangelo Geppetti,Stanislao Rizzo,Pablo Pandolfo,Nicoletta Cini,Malvin N Janal

doi:10.1038/s41419-020-02863-6

Abstract

Oxidative stress is implicated in retinal cell injury associated with glaucoma and other retinal diseases. However, the mechanism by which oxidative stress leads to retinal damage is not completely understood. Transient receptor potential ankyrin 1 (TRPA1) is a redox-sensitive channel that, by amplifying the oxidative stress signal, promotes inflammation and tissue injury. Here, we investigated the role of TRPA1 in retinal damage evoked by ischemia (1 hour) and reperfusion (I/R) in mice. In wild-type mice, retinal cell numbers and thickness were reduced at both day-2 and day-7 after I/R. By contrast, mice with genetic deletion of TRPA1 were protected from the damage seen in their wild-type littermates. Daily instillation of eye drops containing two different TRPA1 antagonists, an oxidative stress scavenger, or a NADPH oxidase-1 inhibitor also protected the retinas of C57BL/6J mice exposed to I/R. Mice with genetic deletion of the proinflammatory TRP channels, vanilloid 1 (TRPV1) or vanilloid 4 (TRPV4), were not protected from I/R damage. Surprisingly, genetic deletion or pharmacological blockade of TRPA1 also attenuated the increase in the number of infiltrating macrophages and in the levels of the oxidative stress biomarker, 4-hydroxynonenal, and of the apoptosis biomarker, active caspase-3, evoked by I/R. These findings suggest that TRPA1 mediates the oxidative stress burden and inflammation that result in murine retinal cell death. We also found that TRPA1 (both mRNA and protein) is expressed by human retinal cells. Thus, it is possible that inhibition of a TRPA1-dependent pathway could also attenuate glaucoma-related retinal damage.

Highlights

Glaucoma is the most common optic neuropathy potentially causing blindness worldwide[1]
We show in a mouse model of retinal damage that genetic deletion or pharmacological blockade of Transient receptor potential ankyrin 1 (TRPA1) attenuated the increase in the apoptosis biomarker, active caspase-3, reduced retinal cell death and preserved retinal tissue thickness
TRPA1-positive staining was observed throughout the retinal layers and in dorsal root ganglia (DRG) neurons of wild-type (Trpa1+/+) mice, but not in retinas or DRG neurons taken from Trpa1−/− mice (Fig. 1b; Supplementary Fig. 1c)

Summary

Introduction

Glaucoma is the most common optic neuropathy potentially causing blindness worldwide[1]. Increased intraocular pressure (IOP), the major risk factor for glaucoma and the object of therapeutic intervention in glaucoma patients, can elicit retinal ischemia and the loss of retinal ganglion cells[2], reduced visual acuity and eventually, blindness[1,2,3]. In a commonly used model of glaucoma, ischemia, and reperfusion (I/R) in rodent retina[7] is associated with increased reactive oxygen species (ROS) levels, tissue damage and cell death[3]. Increased oxidant levels have been proposed as the causal factor of glaucomatous retinal ganglion cell loss[8,9,10,11], an explanation that is supported by data showing that administration of antioxidants protects retinal cells from injury following retinal I/R12–15.

Methods

Results

Conclusion