FT011, a Novel Cardiorenal Protective Drug, Reduces Inflammation, Gliosis and
Vascular Injury in Rats with Diabetic Retinopathy
#MMPMID26222724
Deliyanti D
; Zhang Y
; Khong F
; Berka DR
; Stapleton DI
; Kelly DJ
; Wilkinson-Berka JL
PLoS One
2015[]; 10
(7
): e0134392
PMID26222724
show ga
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 ?M)
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 ?M) 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.
free
free
free
