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Connexin43 hemichannel block protects against the development of diabetic retinopathy signs in a mouse model of the disease

Abstract

Diabetic retinopathy (DR) is a vascular disease of the neuroretina characterised by hyperglycaemia and inflammation. Current DR therapies target late-stage vascular defects and there is evidence to suggest that they contribute to geographic atrophy and retinal ganglion cell death long term. Therefore, alternative treatments that target common upstream disease mechanisms are needed. Recent studies have shown that connexin43 hemichannel blockers can reduce inflammation and prevent vessel leak in brain and spinal cord lesions. The aim of this study was to evaluate the effectiveness of a connexin43 hemichannel blocker (Peptide5) in a mouse model of DR in which pro-inflammatory cytokines, IL-1β and TNF-α, were intravitreally injected into non-obese diabetic (NOD, hyperglycaemic) mice. Fundus and optical coherence tomography images were taken to evaluate vessel dilation and beading as well as retinal and vitreous hyper-reflective foci (HRF). Immunohistochemistry was performed to assess levels of astrogliosis, microgliosis and inflammasome activation. Results showed that Peptide5 injection lowered the incidence of vessel dilation and beading, decreased the severity of vitreous and retinal HRF, and reduced sub-retinal fluid accumulation compared to the vehicle group. Furthermore, Peptide5 led to reduced connexin43 and GFAP upregulation, inhibited microglial infiltration into the outer nuclear layer and prevented upregulation of inflammasome markers compared to vehicle. The present study provides evidence in support of Peptide5, and connexin43 hemichannel block in general, as a potential upstream approach for the treatment of DR.

Key messages

  • Connexin43 is upregulated in a novel mouse model of diabetic retinopathy (DR).

  • Connexin43 hemichannel block inhibits inflammation and inflammasome activation.

  • Connexin43 hemichannel block prevents the development of clinical DR signs.

  • Connexin43 hemichannel block is a potential upstream approach for DR treatment.

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Acknowledgements

O.O.M. was supported by a doctoral scholarship from the Buchanan Ocular Therapeutics Unit, University of Auckland, New Zealand.

Funding

The study was partially funded by a Lottery Health Research Grant, Department of Internal Affairs, and an Auckland Medical Research Foundation Grant [1117015], New Zealand. C.R.G. holds the W&B Hadden Chair in Ophthalmology.

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Correspondence to Ilva D. Rupenthal.

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Mugisho, O.O., Green, C.R., Squirrell, D.M. et al. Connexin43 hemichannel block protects against the development of diabetic retinopathy signs in a mouse model of the disease. J Mol Med 97, 215–229 (2019). https://doi.org/10.1007/s00109-018-1727-5

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  • DOI: https://doi.org/10.1007/s00109-018-1727-5

Keywords

  • Diabetic retinopathy
  • Mouse models
  • Connexin43
  • Hemichannels
  • Inflammation