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A Mouse Model of Retinal Ischemia-Reperfusion Injury Through Elevation of Intraocular Pressure
Published on: July 14, 2016
Disruption of the complement cascade delays retinal ganglion cell death following retinal ischemia-reperfusion
Markus H Kuehn1, Chan Y Kim, Bing Jiang
1Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA 52242, USA. markus-kuehn@uiowa.edu
Insights
Complement cascade activation contributes to retinal ganglion cell (RGC) death after ischemic injury. Disrupting complement component 3 (C3) significantly preserved RGC and reduced optic nerve damage in a mouse model.
Area of Science:
- Ophthalmology
- Neuroscience
- Immunology
Background:
- Complement cascade components are synthesized during retinal ganglion cell (RGC) degeneration in glaucoma.
- Complement activation in the retina may aid phagocytosis of damaged RGC but can also drive neuronal loss in neurodegenerative conditions.
Purpose of the Study:
- To investigate if disrupting the complement cascade impacts RGC survival following retinal ischemia-reperfusion (I/R) injury.
- To determine the role of complement component 3 (C3) in RGC degeneration after I/R.
Main Methods:
- Induction of retinal ischemia-reperfusion (I/R) injury in wild-type and C3-deficient mice.
- Quantitative PCR and immunohistochemistry to assess retinal complement synthesis.
- Histological examination of optic nerve and retina to evaluate RGC death and axon loss.
Main Results:
- Retinal I/R induced expression and deposition of complement components.
- C3-deficient mice showed significantly reduced optic nerve damage and preserved RGC at 1 week post-I/R (p=0.005).
- While optic nerve damage was similar at 3 weeks, C3-deficient mice retained more RGC cell bodies.
Conclusions:
- Inhibition of the complement cascade, specifically C3, delays axonal and RGC degeneration in a murine model of retinal I/R injury.
- These findings suggest that injured RGC are actively destroyed via complement-mediated processes.
- The results highlight the potential role of the complement cascade in ischemic retinal conditions and suggest therapeutic implications.
Abstract:
Recent reports have indicated that components of the complement cascade are synthesized during the degeneration of retinal ganglion cells (RGC) in glaucoma. While complement deposition in the retina may simply serve to aid phagocytosis of damaged RGC, activation of the complement cascade can also contribute to neuronal loss in neurodegenerative diseases. This study was designed to determine if disruption of the complement cascade affects RGC survival in a murine model of retinal ischemia-reperfusion (I/R) injury. We induced retinal ischemia in the eyes of normal mice and mice with a targeted disruption of the complement component 3 (C3) gene. Tissue was harvested 7 and 21 days after induction of I/R and retinal complement synthesis was determined by quantitative PCR and immunohistochemical methods. RGC death and associated axon loss was evaluated through histological examination of the optic nerve and retina. Our data show that retinal I/R induces the expression and deposition of complement components. C3 deficient mice clearly exhibited reduced optic nerve damage and substantial preservation of RGC 1 week after I/R when compared to normal animals (p=0.005). Three weeks after the ischemic event C3 deficient mice retained more RGC cell bodies although the degree of optic nerve damage was similar between both groups. These findings demonstrate that inhibition of the complement cascade delays optic nerve axonal and RGC degeneration in retinal I/R. It appears that injured RGC are targeted and actively destroyed through complement mediated processes. These results may have implications for the pathophysiology and clinical management of ischemic retinal conditions.
