Effect of Fenofibrate on the Expression of Inflammatory Mediators in Animal Model of Diabetic Retinopathy

Diabetic retinopathy (DR) is an important cause of vision loss in patients with diabetes. It’s characterized by increased vascular permeability at initial stage, and then progresses to vascular closure with ischemia. At proliferative stage, abnormal new vessels grow on retina and result in vitreous hemorrhage and tractional retinal detachment 1.Recently, many studies aimed to verify cytokines related to DR, and some cytokines had been identified in previous studies.ytokines related to angiogenesis was found to be potential factors that induced DR. Vascular endothelial growth factor (VEGF) was proved to be an important cytokine involved in DR in many studies. Another group of chemokines which may induce DR is proinflammatory cytokines. Monocyte chemoattractant protein-1 (MCP-1) and the chemokines regulated on activation, normal T-cell expressed and presumably secreted (RANTES)/CCL5 are proinflammatory cytokines that may induce DR.diponectin, a well-known adipocytokine which is closely related to metabolic syndrome6, had also been studied to find its effect on DR. Controversial results were reported in limited studies. All these studies only survey the relationship between “serum” adiponectin and the severity of DR. The relationship between vitreoretinal adiponectin level and the severity of DR had not been investigated in human or animal studies before.esides, results from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study (Lancet 2007) showed beneficial effects of fenofibrate (peroxisome proliferator-activated receptor-alpha (PPAR-α) agonist) in reducing the requirement for panretinal photocoagulation in patients with DR, and particularly in preventing disease progression in patients with pre-existing diabetic retinopathy. The mechanism is not fully understood. Another study showed that fenofibrate can inhibit inflammatory responses associated with NF-κB pathway in kidneys from diabetic rats. Based on the concept that DR is a NF-κB-related inflammatory disease, we hypothesize fenofibrate may prevent the progression of DR via inhibit NF-κB-related inflammation. We conduct a diabetic rat model study to confirm the above hypothesis. We also want to use the same model to identify the expression of adiponectin and its receptors in diabetic rats’ vitreous and retina.n our study, female Wistar rats were divided into 3 groups: normal control, diabetic control, and diabetic + fenofibrate (10 in each group). Diabetes is induced by intraperitoneal injection of streptozotocin (STZ). Blood, vitreous, and retina samples of these rats are collected. Enzyme-linked immunosorbent assay (ELISA), reverse transcription-polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry (IHC) will be performed to study the expression of adiponectin, adiponectin receptors, NF-κB P65, intercelullar adhesion molecule (ICAM)-1, MCP-1 and fractalkine (FKN).ur results showed that the mRNA and protein expression of NF-κB P65, MCP-1 and fractalkine (FKN) were significantly higher in diabetic rats than those in normal control. Treatment with fenofibrate inhibited the increased expression of these factors in diabetic rats’ retina. Protein expression (Western blotting and IHC) of ICAM-1 showed similar trend as above. However, diabetic control and normal control have similar level of ICAM-1 in mRNA level. Treatment with fenofibrate can even increase the expression of ICAM-1 mRNA.esides, diabetic control had increased expression of adiponectin and adiponectin receptors (R1 and R2) than normal control, both in mRNA and protein levels. Treatment with fenofibrate inhibited the increased expression of adiponectin and its receptors (R1 and R2) in diabetic rats’ retina.ccording to the results of our study, inflammatory chemokines mediated by NF-κB had increased expression in diabetic rats, and treatment with fenofibrate can inhibit these reactions. NF-κB-mediated inflammation is a key factor of progression of DR. Fenofibrate therefore has the potential to prevent DR progression. It can also explained the results in FIELD study – taking fenofibrate daily has beneficial effect in reducing the requirement for panretinal photocoagulation in patients with DR.n the future, we will try different doses of fenofibrate and different kinds of PPAR-α agonists in different settings, including in vitro, in vivo, and clinical trials. We hope we can find new medical treatment for diabetic retinopathy and save these patients’vision.