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FT011, a Novel Cardiorenal Protective Drug, Reduces Inflammation, Gliosis and Vascular Injury in Rats with Diabetic Retinopathy.

Deliyanti D, Zhang Y, Khong F, Berka DR, Stapleton DI, Kelly DJ, Wilkinson-Berka JL - PLoS ONE (2015)

Bottom Line: Macroglial Müller cells, which exhibit a pro-inflammatory and pro-angiogenic phenotype in diabetes, were evaluated in the 8-week study as well as in culture following exposure to hyperglycaemia and FT011 (10, 30, 100 μM) for 72 hours.In Müller cells, FT011 reduced diabetes-induced gliosis and vascular endothelial growth factor (VEGF) immunolabeling and the hyperglycaemic-induced increase in ICAM-1, monocyte chemoattractant protein-1, CCL20, cytokine-induced neutrophil chemoattractant-1, VEGF and IL-6.In conclusion, the protective effects of FT011 in cardiorenal disease extend to key elements of diabetic retinopathy and highlight its potential as a treatment approach.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia, 3004.

ABSTRACT
Diabetic retinopathy features inflammation as well as injury to glial cells and the microvasculature, which are influenced by hypertension and overactivity of the renin-angiotensin system. FT011 is an anti-inflammatory and anti-fibrotic agent that has been reported to attenuate organ damage in diabetic rats with cardiomyopathy and nephropathy. However, the potential therapeutic utility of FT011 for diabetic retinopathy has not been evaluated. We hypothesized that FT011 would attenuate retinopathy in diabetic Ren-2 rats, which exhibit hypertension due to an overactive extra-renal renin-angiotensin system. Diabetic rats were studied for 8 and 32 weeks and received intravitreal injections of FT011 (50 μM) or vehicle (0.9% NaCl). Comparisons were to age-matched controls. In the 8-week study, retinal inflammation was examined by quantitating vascular leukocyte adherence, microglial/macrophage density and the expression of inflammatory mediators. Macroglial Müller cells, which exhibit a pro-inflammatory and pro-angiogenic phenotype in diabetes, were evaluated in the 8-week study as well as in culture following exposure to hyperglycaemia and FT011 (10, 30, 100 μM) for 72 hours. In the 32-week study, severe retinal vasculopathy was examined by quantitating acellular capillaries and extracellular matrix proteins. In diabetic rats, FT011 reduced retinal leukostasis, microglial density and mRNA levels of intercellular adhesion molecule-1 (ICAM-1). In Müller cells, FT011 reduced diabetes-induced gliosis and vascular endothelial growth factor (VEGF) immunolabeling and the hyperglycaemic-induced increase in ICAM-1, monocyte chemoattractant protein-1, CCL20, cytokine-induced neutrophil chemoattractant-1, VEGF and IL-6. Late intervention with FT011 reduced acellular capillaries and the elevated mRNA levels of collagen IV and fibronectin in diabetic rats. In conclusion, the protective effects of FT011 in cardiorenal disease extend to key elements of diabetic retinopathy and highlight its potential as a treatment approach.

No MeSH data available.


Related in: MedlinePlus

FT011M reduced VEGF immunolabeling in retina of Ren-2 rats diabetic for 8 weeks.Non-diab, non-diabetic. Diab, diabetic. V, vehicle. Three-μm paraffin sections. GCL, ganglion cell layer. IPL, inner plexiform layer. INL, inner nuclear layer. ONL, outer nuclear layer. Counterstain, haematoxylin. (A). In non-diab + V, VEGF immunolabeling is occasionally detected in ganglion cells (arrowheads) in the GCL. (B) In diab + V, VEGF immunolabeling is increased compared to non-diab + V and detected in ganglion cells and Müller cell processes (arrows) extending throughout the retina. Inset showing higher powered image of Müller cell processes. (C) In diabetic rats treated with FT011M, VEGF immunolabeling was reduced to the level of non-diab + V. (A to C) Original magnification, 400X. Bar, 40 μm. Inset: Bar, 75 μm. (D) **P < 0.01 to non-diab + V. ##P < 0.01 to diab + V. N = 4 to 6 rats per group. Values are Mean ± SEM.
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pone.0134392.g004: FT011M reduced VEGF immunolabeling in retina of Ren-2 rats diabetic for 8 weeks.Non-diab, non-diabetic. Diab, diabetic. V, vehicle. Three-μm paraffin sections. GCL, ganglion cell layer. IPL, inner plexiform layer. INL, inner nuclear layer. ONL, outer nuclear layer. Counterstain, haematoxylin. (A). In non-diab + V, VEGF immunolabeling is occasionally detected in ganglion cells (arrowheads) in the GCL. (B) In diab + V, VEGF immunolabeling is increased compared to non-diab + V and detected in ganglion cells and Müller cell processes (arrows) extending throughout the retina. Inset showing higher powered image of Müller cell processes. (C) In diabetic rats treated with FT011M, VEGF immunolabeling was reduced to the level of non-diab + V. (A to C) Original magnification, 400X. Bar, 40 μm. Inset: Bar, 75 μm. (D) **P < 0.01 to non-diab + V. ##P < 0.01 to diab + V. N = 4 to 6 rats per group. Values are Mean ± SEM.

Mentions: In non-diabetic Ren-2 rats immunolabeling for VEGF was detected in occasional ganglion cells, whilst in untreated diabetic Ren-2 rats, VEGF immunolabeling was increased and present in ganglion cells and Müller cell processes extending throughout the retina (Fig 4). The treatment of diabetic Ren-2 rats with FT011M reduced VEGF immunolabeling in ganglion cells and Müller cells (Fig 4).


FT011, a Novel Cardiorenal Protective Drug, Reduces Inflammation, Gliosis and Vascular Injury in Rats with Diabetic Retinopathy.

Deliyanti D, Zhang Y, Khong F, Berka DR, Stapleton DI, Kelly DJ, Wilkinson-Berka JL - PLoS ONE (2015)

FT011M reduced VEGF immunolabeling in retina of Ren-2 rats diabetic for 8 weeks.Non-diab, non-diabetic. Diab, diabetic. V, vehicle. Three-μm paraffin sections. GCL, ganglion cell layer. IPL, inner plexiform layer. INL, inner nuclear layer. ONL, outer nuclear layer. Counterstain, haematoxylin. (A). In non-diab + V, VEGF immunolabeling is occasionally detected in ganglion cells (arrowheads) in the GCL. (B) In diab + V, VEGF immunolabeling is increased compared to non-diab + V and detected in ganglion cells and Müller cell processes (arrows) extending throughout the retina. Inset showing higher powered image of Müller cell processes. (C) In diabetic rats treated with FT011M, VEGF immunolabeling was reduced to the level of non-diab + V. (A to C) Original magnification, 400X. Bar, 40 μm. Inset: Bar, 75 μm. (D) **P < 0.01 to non-diab + V. ##P < 0.01 to diab + V. N = 4 to 6 rats per group. Values are Mean ± SEM.
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pone.0134392.g004: FT011M reduced VEGF immunolabeling in retina of Ren-2 rats diabetic for 8 weeks.Non-diab, non-diabetic. Diab, diabetic. V, vehicle. Three-μm paraffin sections. GCL, ganglion cell layer. IPL, inner plexiform layer. INL, inner nuclear layer. ONL, outer nuclear layer. Counterstain, haematoxylin. (A). In non-diab + V, VEGF immunolabeling is occasionally detected in ganglion cells (arrowheads) in the GCL. (B) In diab + V, VEGF immunolabeling is increased compared to non-diab + V and detected in ganglion cells and Müller cell processes (arrows) extending throughout the retina. Inset showing higher powered image of Müller cell processes. (C) In diabetic rats treated with FT011M, VEGF immunolabeling was reduced to the level of non-diab + V. (A to C) Original magnification, 400X. Bar, 40 μm. Inset: Bar, 75 μm. (D) **P < 0.01 to non-diab + V. ##P < 0.01 to diab + V. N = 4 to 6 rats per group. Values are Mean ± SEM.
Mentions: In non-diabetic Ren-2 rats immunolabeling for VEGF was detected in occasional ganglion cells, whilst in untreated diabetic Ren-2 rats, VEGF immunolabeling was increased and present in ganglion cells and Müller cell processes extending throughout the retina (Fig 4). The treatment of diabetic Ren-2 rats with FT011M reduced VEGF immunolabeling in ganglion cells and Müller cells (Fig 4).

Bottom Line: Macroglial Müller cells, which exhibit a pro-inflammatory and pro-angiogenic phenotype in diabetes, were evaluated in the 8-week study as well as in culture following exposure to hyperglycaemia and FT011 (10, 30, 100 μM) for 72 hours.In Müller cells, FT011 reduced diabetes-induced gliosis and vascular endothelial growth factor (VEGF) immunolabeling and the hyperglycaemic-induced increase in ICAM-1, monocyte chemoattractant protein-1, CCL20, cytokine-induced neutrophil chemoattractant-1, VEGF and IL-6.In conclusion, the protective effects of FT011 in cardiorenal disease extend to key elements of diabetic retinopathy and highlight its potential as a treatment approach.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia, 3004.

ABSTRACT
Diabetic retinopathy features inflammation as well as injury to glial cells and the microvasculature, which are influenced by hypertension and overactivity of the renin-angiotensin system. FT011 is an anti-inflammatory and anti-fibrotic agent that has been reported to attenuate organ damage in diabetic rats with cardiomyopathy and nephropathy. However, the potential therapeutic utility of FT011 for diabetic retinopathy has not been evaluated. We hypothesized that FT011 would attenuate retinopathy in diabetic Ren-2 rats, which exhibit hypertension due to an overactive extra-renal renin-angiotensin system. Diabetic rats were studied for 8 and 32 weeks and received intravitreal injections of FT011 (50 μM) or vehicle (0.9% NaCl). Comparisons were to age-matched controls. In the 8-week study, retinal inflammation was examined by quantitating vascular leukocyte adherence, microglial/macrophage density and the expression of inflammatory mediators. Macroglial Müller cells, which exhibit a pro-inflammatory and pro-angiogenic phenotype in diabetes, were evaluated in the 8-week study as well as in culture following exposure to hyperglycaemia and FT011 (10, 30, 100 μM) for 72 hours. In the 32-week study, severe retinal vasculopathy was examined by quantitating acellular capillaries and extracellular matrix proteins. In diabetic rats, FT011 reduced retinal leukostasis, microglial density and mRNA levels of intercellular adhesion molecule-1 (ICAM-1). In Müller cells, FT011 reduced diabetes-induced gliosis and vascular endothelial growth factor (VEGF) immunolabeling and the hyperglycaemic-induced increase in ICAM-1, monocyte chemoattractant protein-1, CCL20, cytokine-induced neutrophil chemoattractant-1, VEGF and IL-6. Late intervention with FT011 reduced acellular capillaries and the elevated mRNA levels of collagen IV and fibronectin in diabetic rats. In conclusion, the protective effects of FT011 in cardiorenal disease extend to key elements of diabetic retinopathy and highlight its potential as a treatment approach.

No MeSH data available.


Related in: MedlinePlus