Abstract
Purpose: :
The synthetic retinoid fenretinide (HPR) is known to inhibit VEGF- and FGF-2-induced endothelial cell proliferation and to inhibit angiogenesis in vivo in the chick chorioallantoic membrane. The present study was conducted to determine whether HPR can reduce retinal pathology and angiogenesis in a diabetes animal model.
Methods: :
The retinas of male mice heterozygous for the insulin 2 gene (Ins2Akita) exhibit vascular, neural, and glial abnormalities generally consistent with clinical observations and other animal models of diabetes. Ins2Akita littermates (aged 8 weeks) were divided into two groups. One group received a rodent diet containing HPR (0.1%, w/w). The second group received an unsupplemented rodent chow. Mice ingested these diets ad libitum for 8 weeks. Blood glucose was routinely monitored. At the end of the treatment period, mice were euthanized and eyecups were prepared for biochemical and immunohistochemical analyses.
Results: :
HPR-treatment had no effect on blood glucose levels. Both groups of Ins2Akita mice demonstrated ~ 5-fold increase in blood glucose compared to strain and age-matched wild type mice. As expected, there was a significant reduction of RBP-retinol (~ 70%) in the HPR-treated group compared to control. HPLC analysis of ocular tissue extracts showed ~ 20 pmoles HPR/eye in the treated group. Immunohistochemical analyses confirmed the presence of inflammatory and angiogenic biomarkers in the control group (i.e., strong immunoreactivity for advanced glycation end products and their receptors, vascular endothelial cadherin, phosphorylated p38 MAPK, and VEGF). Strikingly, the presence of these biomarkers was significantly reduced in the HPR-treated group.
Conclusions: :
Our data support previous findings of anti-angiogenic and anti-inflammatory effects of HPR. Notably, Ins2Akita mutation is correlated with ~ 50% reduction in serum RBP-retinol. Despite this significantly reduced serum RBP-retinol, there is pronounced retinal pathology in the absence of HPR treatment. This suggests that the therapeutic efficacy of HPR observed in this study is not due to HPR-mediated reductions of serum RBP-retinol. Investigation of the mechanism of action for HPR in this disease indication is currently in progress.
Keywords: diabetic retinopathy • neovascularization • inflammation