title: FT011, a Novel Cardiorenal Protective Drug, Reduces Inflammation, Gliosis and Vascular Injury in Rats with Diabetic Retinopathy.
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.
authors.affiliation: Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia, 3004.
authors.forename: Devy
authors.initials: D
authors.lastname: Deliyanti
authors.affiliation: Department of Medicine, St Vincent's Hospital, The University of Melbourne, Fitzroy, Victoria, Australia, 3065.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Medicine, St Vincent's Hospital, The University of Melbourne, Fitzroy, Victoria, Australia, 3065.
authors.forename: Fay
authors.initials: F
authors.lastname: Khong
authors.affiliation: Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia, 3004.
authors.forename: David R
authors.initials: DR
authors.lastname: Berka
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia, 3052.
authors.forename: David I
authors.initials: DI
authors.lastname: Stapleton
authors.affiliation: Department of Medicine, St Vincent's Hospital, The University of Melbourne, Fitzroy, Victoria, Australia, 3065.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
authors.affiliation: Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia, 3004.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Wilkinson-Berka
mesh_terms: D000818:Animals; D002109:Caffeic Acids / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D063928:Ependymoglial Cells; D005260:Female; D005911:Gliosis / Q000188:drug therapy* / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1; D015850:Interleukin-6 / Q000378:metabolism; D018921:Leukostasis / Q000188:drug therapy / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D051381:Rats; D012084:Renin-Angiotensin System / Q000187:drug effects; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D012171:Retinal Vessels / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
chemical_list: C111835:CCL2 protein, human; D002109:Caffeic Acids; D018932:Chemokine CCL2; C576235:FT011; D015850:Interleukin-6; D020011:Protective Agents; D042461:Vascular Endothelial Growth Factor A; D062367:ortho-Aminobenzoates; D018799:Intercellular Adhesion Molecule-1