Caveolin-1 Ablation Imparts Partial Protection Against Inner Retinal Injury in Experimental Glaucoma and Reduces Apoptotic Activation

Abstract

Retinal ganglion cell degeneration is a characteristic feature of glaucoma, and accordingly, protection of these cells constitutes a major therapeutic objective in the disease. Here, we demonstrate the key influence of caveolin (Cav) in regulating the inner retinal homeostasis in two models of experimentally elevated intraocular pressure (IOP). Two groups of Cav-1−/− and wild-type mice were used in the study. Animals were subjected to experimentally induced chronic and acutely elevated IOP and any changes in their retinal function were assessed by positive scotopic threshold response recordings. TUNEL and cleaved caspase-3 assays were performed to evaluate apoptotic changes in the retina while Brn3a immunostaining was used as a marker to assess and quantify ganglion cell layer (GCL) changes. H&E staining was carried out on retinal sections to evaluate histological differences in retinal laminar structure. Cav-1 ablation partially protected the inner retinal function in both chronic and acute models of elevated IOP. The protective effects of Cav-1 loss were also evident histologically by reduced loss of GCL density in both models. The phenotypic protection in Cav-1−/− glaucoma mice paralleled with increased TrkB phosphorylation and reduced endoplasmic reticulum stress markers and apoptotic activation in the inner retinas. This study corroborated previous findings of enhanced Shp2 phosphorylation in a chronic glaucoma model and established a novel role of Cav-1 in mediating activation of this phosphatase in the inner retina in vivo. Collectively, these findings highlight the critical involvement of Cav-1 regulatory mechanisms in ganglion cells in response to increased IOP, implicating Cav-1 as a potential therapeutic target in glaucoma.

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Acknowledgements

We acknowledge the funding bodies and apologise for not being able to cite many other relevant references.

Funding

This work was supported by the National Health and Medical Research Council (NHMRC) of Australia (grants APP1140064 and APP1150083 and fellowship APP1156489 to R.G.P.), Ophthalmic Research Institute of Australia (ORIA) and Macquarie University, NSW, Australia. RGP is supported by the Australian Research Council (ARC) Centre of Excellence in Convergent Bio-Nano Science and Technology.

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Correspondence to Vivek K. Gupta or Nitin Chitranshi.

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All the animal experimental work performed in the current study was approved by the Macquarie University Animal Ethics Committee in Australia.

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Fig. S1.
figure12

Representative immunohistochemical images of the retinal sections stained with Cav-1 antibody. (a,b) WT and Cav 1-/- retinas stained with Cav-1 antibody following chronic and acute IOP injury. Blue-Dapi, Red- Cav-1 staining. n=3 each group, Scale bar= 50μm. (PNG 2181 kb)

Fig. S2.
figure13

ERG responses from WT and Cav-1-/-mice. (a-c) Representative whole retinal scotopic ERG traces from WT and Cav-1-/- mice at 4, 6 and 12 weeks of age respectively. (d-f) ERG quantification of a- and b-wave amplitudes at all the three time points (n=18 each group). Error bars indicate mean ± SD. (PNG 136 kb)

Fig. S3.
figure14

Effects of increased IOP on TrkB and Shp2 expression in WT and Cav-1-/-mice retinas (a-b) TrkB and (c, d) Shp2 expression changes in WT and Cav-1-/- mice retinas in both chronic and acute models of experimental glaucoma (n=3 per group). (e-g) Western blotting and densitometric analysis of the band intensities for TrkB and Shp2 expression changes in ONH lysates in both models of experimental glaucoma. GAPDH was used an internal control and data quantification carried out within the linear range of detection. n=4 each group. (PNG 2595 kb)

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Table S1:

The combined set of proteins identified from the retina of Cav-1 KO and WT mice, as well as the list of differentially expressed proteins obtained from a t-test comparison between CAV-1 KO vs WT (p ≤ 0.05 and ratio fold change >1.20). (XLSX 1641 kb)

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Abbasi, M., Gupta, V.K., Chitranshi, N. et al. Caveolin-1 Ablation Imparts Partial Protection Against Inner Retinal Injury in Experimental Glaucoma and Reduces Apoptotic Activation. Mol Neurobiol (2020). https://doi.org/10.1007/s12035-020-01948-9

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Keywords

  • Caveolin
  • Glaucoma
  • Retinal ganglion cells
  • TrkB receptor
  • Apoptosis