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Jurgen Sergeys, Isabelle Etienne, Evy Lefevere, Inge Van Hove, Tine Van Bergen, Lies De Groef, Michaël Porcu, Jean Feyen, Lieve K M Moons; A potential role for Src during early experimental diabetic retinopathy?. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2783. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetic retinopathy (DR) is historically classified as a microvascular complication of diabetes mellitus. However, recent evidence suggests that also inflammation and neurodegeneration importantly contribute to DR, and may even manifest early in DR pathogenesis. Kinases, such as Src, appear to be important regulators at the crossroad of these cellular processes in several eye diseases and might be potential drugable targets for an integrated DR therapy. This study aimed to (i) longitudinally characterize these pathological hallmarks, and (ii) study the activation of Src kinase, in the streptozotocin (STZ)-induced diabetes mouse model.
Diabetes was induced in male C57Bl/6J mice via intraperitoneal injection of STZ for 5 consecutive days. Visual acuity was studied bi-weekly, from 0 till 8 weeks post-diabetes onset. At the same time points, electroretinography (ERG), optical coherence tomography (OCT), leukostasis and immunohistochemical stainings were used to investigate neurodegeneration, inflammation and gliosis. To determine the activation of Src, total and phospho (p)-Src levels were quantified via Western blotting.
Diabetic mice displayed progressive visual acuity loss from 4 weeks post-diabetes onset. At 6 weeks, ERG b-wave amplitude was diminished and oscillatory potential 2 (OP2) latency was increased, and these changes progressively deteriorated over time. OCT revealed thinning of nerve fiber and ganglion cell layers from 4 weeks onwards, and of the total neuronal retina at 8 weeks post-diabetes. Immunohistochemistry linked the above findings to retinal ganglion and amacrine cell loss at 4 and 8 weeks post-diabetes, respectively. Assays for inflammation showed increased numbers of adherent leukocytes after 2 weeks, and micro- and macroglia activation at 4 weeks post-diabetes. Quantification of the p-Src versus total Src ratio showed that Src activation was elevated at 4, 6 and 8 weeks post-diabetes. We are currently performing pharmacological inhibition studies to further investigate the role of Src during early-stage DR.
The STZ diabetic mouse model develops early DR hallmarks, including inflammation and neurodegeneration, that lead to loss of visual function. Moreover, elevated p-Src levels suggest a crucial role for this kinase during the early stage of DR development. Moreover, in-depth experiments can denote Src as an innovative target to treat patients during early-stage DR.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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