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Jennifer L Wilkinson-Berka, Devy Deliyanti, Yuan Zhang, Fay Khong, David Berka, David Ian Stapelton, Darren Kelly; FT011, a novel cardiorenal protective drug, reduces inflammation, gliosis and vascular injury in rats with diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4674.
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© ARVO (1962-2015); The Authors (2016-present)
We previously demonstrated that the anti-inflammatory and anti-fibrotic agent, FT011, attenuated cardiomyopathy and nephropathy in diabetic rats. Here, we hypothesized that FT011 would have beneficial effects in diabetic retinopathy by reducing inflammation, gliosis and vascular injury.
Diabetic Ren-2 rats were studied for 8 and 32 weeks. In the 8-week study, rats received intravitreal injections of FT011 meglamine salt (FT011, 50 μM) or vehicle (0.9% NaCl) after 2 days and 4 weeks of diabetes. In the 32-week study, rats were treated after retinopathy was established at 16, 20, 24 and 28 weeks. Comparisons were to age-matched controls. In the 8-week study, retinal inflammation was examined by quantitating vascular leukocyte adherence (n=5-6 rats/group), microglial density with ionized calcium binding adaptor protein-1 immunohistochemistry (n=4-6 rats/group) and inflammatory mediators with quantitative RT-PCR (n=8-9 rats/group). Macroglial Müller cells, which become injured in diabetes, were evaluated in the 8-week study with immunohistochemistry for glial fibrillary acidic protein and vascular endothelial growth factor (VEGF) (n=4-6 rats/group). Müller cells were evaluated in primary culture following exposure to hyperglycaemia and FT011 (10, 30, 100 μM) for 72 hours and inflammatory and angiogenic mediators measured by protein array and ELISA (n=3/group in triplicate). In the 32-week study, vasculopathy was examined by quantitating acellular capillaries in trypsin digests of retina (n=8-11 rats/group).
In diabetic rats, retinal inflammation, which was increased compared to non-diabetic rats, was reduced with FT011 and included leukostasis (p<0.05), microglial density (p<0.01) and mRNA for intercellular adhesion molecule-1 (ICAM-1, p<0.05). In diabetic rats, FT011 protected Müller cells from gliosis (p<0.001) and increased VEGF immunolabeling (p<0.01), and in culture the hyperglycaemic-induced increase in protein expression of ICAM-1, monocyte chemoattractant protein-1, CCL20, cytokine-induced neutrophil chemoattractant-1, VEGF and interleukin-6. Late intervention with FT011 reduced acellular capillaries in diabetic rats (p<0.05).
The protective effects of FT011 in cardiorenal disease extend to key elements of diabetic retinopathy and highlight its potential as a treatment approach.
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