Knock-Out of Tenascin-C Ameliorates Ischemia-Induced Rod-Photoreceptor Degeneration and Retinal Dysfunction

Abstract

Retinal ischemia is a common pathomechanism in various eye diseases. Recently, evidence accumulated suggesting that the extracellular matrix (ECM) glycoprotein tenascin-C (Tnc) plays a key role in ischemic degeneration. However, the possible functional role of Tnc in retinal ischemia is not yet known. The aim of our study was to explore retinal function and rod-bipolar/photoreceptor cell degeneration in wild type (WT) and Tnc knock-out (KO) mice after ischemia/reperfusion (I/R) injury. Therefore, I/R was induced by increasing intraocular pressure in the right eye of wild type (WT I/R) and Tnc KO (KO I/R) mice. The left eye served as untreated control (WT CO and KO CO). Scotopic electroretinogram (ERG) recordings were performed to examine rod-bipolar and rod-photoreceptor cell function. Changes of Tnc, rod-bipolar cells, photoreceptors, retinal structure and apoptotic and synaptic alterations were analyzed by immunohistochemistry, Hematoxylin and Eosin staining, Western blot, and quantitative real time PCR. We found increased Tnc protein levels 3 days after ischemia, while Tnc immunoreactivity decreased after 7 days. Tnc mRNA expression was comparable in the ischemic retina. ERG measurements after 7 days showed lower a-/b-wave amplitudes in both ischemic groups. Nevertheless, the amplitudes in the KO I/R group were higher than in the WT I/R group. We observed retinal thinning in WT I/R mice after 3 and 7 days. Although compared to the KO CO group, retinal thinning was not observed in the KO I/R group until 7 days. The number of PKCα+ rod-bipolar cells, recoverin+ photoreceptor staining and Prkca and Rcvrn expression were comparable in all groups. However, reduced rhodopsin protein as well as Rho and Gnat1 mRNA expression levels of rod-photoreceptors were found in the WT I/R, but not in the KO I/R retina. Additionally, a lower number of activated caspase 3+ cells was observed in the KO I/R group. Finally, both ischemic groups displayed enhanced vesicular glutamate transporter 1 (vGlut1) levels. Collectively, KO mice showed diminished rod-photoreceptor degeneration and retinal dysfunction after I/R. Elevated vGlut1 levels after ischemia could be related to an impaired glutamatergic photoreceptor-bipolar cell signaling and excitotoxicity. Our study provides novel evidence that Tnc reinforces ischemic retinal degeneration, possibly by synaptic remodeling.

Effects of Hydrostatic Pressure on Electrical Retinal Activity in a Multielectrode Array-Based ex vivo Glaucoma Acute Model

“…In contrast, we showed that hypoxic stress has a dramatic effect on the RGCs' electrical activity and their survival rate (Ingensiep et al, 2021). Hypoxia can be induced in vivo by impaired blood flow under high IOP (Andreeva et al, 2014;Wiemann et al, 2021). The findings of our work help to better evaluate and understand the role of pressure stress in glaucoma next to other stressors, such as hypoxia.…”

The Extracellular Matrix Proteins Tenascin-C and Tenascin-R Retard Oligodendrocyte Precursor Maturation and Myelin Regeneration in a Cuprizone-Induced Long-Term Demyelination Animal Model

“…On the other hand, several studies revealed subtle developmental modifications in the radial glia and oligodendrocyte compartments that were compensated for in the adult CNS [ 74 , 75 ]. Furthermore, recent studies suggested functional roles of Tnc in response to lesions, in particular in the CNS [ 76 , 77 , 78 , 79 ], reviewed in [ 80 ]. Therefore, we decided to investigate the roles of Tnc and Tnr in a myelin lesion model based on the application of cuprizone to the chow [ 81 , 82 ].…”

Proteomic Analysis of Retinal Tissue in an S100B Autoimmune Glaucoma Model

“…Previously, an enhanced immunostaining of the ECM proteins Tenascin-C and phosphacan/RPTPβ/ζ was identified in S100B optic nerves after 7 days [ 41 ]. Tenascin-C showed enhanced immunoreactivity in the optic nerve after ischemia-reperfusion injury [ 102 ], while a knockout of Tenascin-C could protect the retinal function and rod-photoreceptor cells from ischemic damage [ 103 ].…”