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.
Highlights
IntroductionRetinal ischemia contributes to the pathophysiology of numerous eye disorders, such as vascular occlusions (e.g., central retinal vein/artery occlusion), acute glaucoma, and diabetic retinopathy (Osborne et al, 2004; Hayreh, 2005; Campochiaro, 2015)
Retinal ischemia contributes to the pathophysiology of numerous eye disorders, such as vascular occlusions, acute glaucoma, and diabetic retinopathy (Osborne et al, 2004; Hayreh, 2005; Campochiaro, 2015)
At 3 days after ischemia, we found a significant increase of the Tnc+ staining area (p < 0.01; Figure 1E)
Summary
Retinal ischemia contributes to the pathophysiology of numerous eye disorders, such as vascular occlusions (e.g., central retinal vein/artery occlusion), acute glaucoma, and diabetic retinopathy (Osborne et al, 2004; Hayreh, 2005; Campochiaro, 2015). The ischemic phase is followed by a natural reperfusion phase in which blood circulation is restored. This leads to further progressive damage of the retina through oxidative stress. Several studies indicate that ischemic neurodegeneration in the retina of different animal models is characterized by a loss of functional activity and loss of various neuronal subtypes (Kaur et al, 2008; Belforte et al, 2011; Joachim et al, 2012; Minhas et al, 2012; Schmid et al, 2014). I/R injury leads to the death of various retinal neurons, since they are sensitive to hypoxic stress (Kaur et al, 2008; Xu et al, 2015; Hu et al, 2016; Schultz et al, 2016; Palmhof et al, 2019)
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