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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 Müller cell gliosis in the retina of Ren-2 rats diabetic for 8 weeks.Non-diab, non-diabetic. Diab, diabetic. V, vehicle. Three-μm paraffin sections. IPL, inner plexiform layer. INL, inner nuclear layer. OPL, outer plexiform layer. ONL, outer nuclear layer. Original magnification, 400X. Bar, 40 μm. (A to C) Central retina. (D to F) Mid retina. (G to I) Peripheral retina. In non-diab + V, GFAP immunolabeling is present on the retinal surface (asterisk) and in Müller cell processes (arrows) extending throughout the retinal layers and in the central, mid and peripheral retina (A, D, G). GFAP immunolabeling is increased in diab + V (B, E, H). In diabetic rats, FT011M reduced GFAP immunolabeling in the central (G), mid (F) and peripheral (I) retina to the level of non-diab + V. (J to M) *P < 0.01 and ***P < 0.001 to non-diab + V. ##P < 0.01 and ###P < 0.001 to diab + V. N = 4 to 6 rats per group. Values are Mean ± SEM.
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pone.0134392.g003: FT011M reduced Müller cell gliosis in the retina of Ren-2 rats diabetic for 8 weeks.Non-diab, non-diabetic. Diab, diabetic. V, vehicle. Three-μm paraffin sections. IPL, inner plexiform layer. INL, inner nuclear layer. OPL, outer plexiform layer. ONL, outer nuclear layer. Original magnification, 400X. Bar, 40 μm. (A to C) Central retina. (D to F) Mid retina. (G to I) Peripheral retina. In non-diab + V, GFAP immunolabeling is present on the retinal surface (asterisk) and in Müller cell processes (arrows) extending throughout the retinal layers and in the central, mid and peripheral retina (A, D, G). GFAP immunolabeling is increased in diab + V (B, E, H). In diabetic rats, FT011M reduced GFAP immunolabeling in the central (G), mid (F) and peripheral (I) retina to the level of non-diab + V. (J to M) *P < 0.01 and ***P < 0.001 to non-diab + V. ##P < 0.01 and ###P < 0.001 to diab + V. N = 4 to 6 rats per group. Values are Mean ± SEM.

Mentions: In non-diabetic rats, GFAP immunolabeling was present at the retinal surface and in Müller cells processes (Fig 3). In untreated diabetic Ren-2 rats, GFAP immunolabeling in Müller cells was markedly increased in the central, mid and peripheral retina compared to age-matched non-diabetic controls (Fig 3). In diabetic Ren-2 rats, FT011M reduced GFAP immunolabeling in all layers and regions of the retina compared to untreated diabetic Ren-2 rats (Fig 3).


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 Müller cell gliosis in the retina of Ren-2 rats diabetic for 8 weeks.Non-diab, non-diabetic. Diab, diabetic. V, vehicle. Three-μm paraffin sections. IPL, inner plexiform layer. INL, inner nuclear layer. OPL, outer plexiform layer. ONL, outer nuclear layer. Original magnification, 400X. Bar, 40 μm. (A to C) Central retina. (D to F) Mid retina. (G to I) Peripheral retina. In non-diab + V, GFAP immunolabeling is present on the retinal surface (asterisk) and in Müller cell processes (arrows) extending throughout the retinal layers and in the central, mid and peripheral retina (A, D, G). GFAP immunolabeling is increased in diab + V (B, E, H). In diabetic rats, FT011M reduced GFAP immunolabeling in the central (G), mid (F) and peripheral (I) retina to the level of non-diab + V. (J to M) *P < 0.01 and ***P < 0.001 to non-diab + V. ##P < 0.01 and ###P < 0.001 to diab + V. N = 4 to 6 rats per group. Values are Mean ± SEM.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4519240&req=5

pone.0134392.g003: FT011M reduced Müller cell gliosis in the retina of Ren-2 rats diabetic for 8 weeks.Non-diab, non-diabetic. Diab, diabetic. V, vehicle. Three-μm paraffin sections. IPL, inner plexiform layer. INL, inner nuclear layer. OPL, outer plexiform layer. ONL, outer nuclear layer. Original magnification, 400X. Bar, 40 μm. (A to C) Central retina. (D to F) Mid retina. (G to I) Peripheral retina. In non-diab + V, GFAP immunolabeling is present on the retinal surface (asterisk) and in Müller cell processes (arrows) extending throughout the retinal layers and in the central, mid and peripheral retina (A, D, G). GFAP immunolabeling is increased in diab + V (B, E, H). In diabetic rats, FT011M reduced GFAP immunolabeling in the central (G), mid (F) and peripheral (I) retina to the level of non-diab + V. (J to M) *P < 0.01 and ***P < 0.001 to non-diab + V. ##P < 0.01 and ###P < 0.001 to diab + V. N = 4 to 6 rats per group. Values are Mean ± SEM.
Mentions: In non-diabetic rats, GFAP immunolabeling was present at the retinal surface and in Müller cells processes (Fig 3). In untreated diabetic Ren-2 rats, GFAP immunolabeling in Müller cells was markedly increased in the central, mid and peripheral retina compared to age-matched non-diabetic controls (Fig 3). In diabetic Ren-2 rats, FT011M reduced GFAP immunolabeling in all layers and regions of the retina compared to untreated diabetic Ren-2 rats (Fig 3).

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