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Lalit P Singh; Glial activation, inflammation, and neuronal injury in diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4919.
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© ARVO (1962-2015); The Authors (2016-present)
(i) To determine whether early glial activation (Muller glia and microglia) is associated with retinal inflammation and neurodegeneration in diabetic retinopathy (DR). (ii) To further investigate if TXNIP knock down by siRNA prevents these retinal abnormalities in DR.
Streptozotocin (STZ)-induced diabetic rats and age-matched normal rats were maintained for 8 and 16 weeks. To knock down TXNIP, siRNA targeted to TXNIP was injected intravitreally in diabetic rats while scramble RNA were used as controls. Subsequently, the rats were sacrificed; retinas harvested, and analyzed for gene expression by real time quantitative PCR, Western blotting and immunohistochemistry.
We observed that the expression of radial glial fibrillary acidic protein (GFAP, marker for Muller cell activation) and iba-1 (microglial activation marker) were increased significantly in the diabetic retina when compared with the normal retina. These results suggested that glial cell activation occured in early DR and they might produce pro-inflammatory cytokines. We found that TXNIP, IL-1beta, and iNOS levels were also increased significantly, suggesting retinal oxidative/nitrosative stress and inflammation in DR. Furthermore, caspase-3 staining were increased in ganglion cell and inner nuclear layers suggesting neuronal injury and death in DR. Knock down of TXNIP by intravitreous siTXNIP treatment prevented several molecular abnormalities in the diabetic rat retina. Interestingly, in vitro, H2O2 and IL-1beta treatment generated excess ROS in rMC1 (a rat Muller cell line) and reduced cell viabilty under low glucose (LG, 5 mM). When high glucose (HG, 25 mM) was added, H2O2 and IL-1beta produced higher ROS in rMC1; however cell viability was maintained.
There was early glial activation and retinal inflammation in DR. They were also associated with retinal neuron death in DR. Blunting TXNIP ameliorated several of these retinal abnormalities in diabetic rats suggesting that reducing glial activation and TXNIP up-regulation may prevent/slow down the progression of late DR such as neurovascular dysfunction and neovascularization.
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