Abstract
The spontaneously diabetic Torii (SDT) rat is of increasing preclinical interest because of its similarities to human type 2 diabetic retinopathy (DR). The system formed by urokinase-type plasminogen activator (uPA) and its receptor (uPAR) is a player in blood-retinal barrier (BRB) breakdown in DR. Here, we investigated whether in SDT rats, preventive administration of UPARANT, an inhibitor of the uPAR pathway, counteracts the retinal impairment in response to chronic hyperglycemia. Electroretinogram (ERG) monitoring was followed over time. Fluorescein-dextran microscopy, CD31 immunohistochemistry, quantitative PCR, ELISA, Evans blue perfusion, and Western blot were also used. UPARANT prevented ERG dysfunction, upregulation of vascular endothelial growth factor and fibroblast growth factor-2, BRB leakage, gliosis, and retinal cell death. The mechanisms underlying UPARANT benefits were studied comparing them with the acute streptozotocin (STZ) model in which UPARANT is known to inhibit DR signs. In SDT rats, but not in the STZ model, UPARANT downregulated the expression of uPAR and its membrane partners. In both models, UPARANT reduced the levels of transcription factors coupled to inflammation or inflammatory factors themselves. These findings may help to establish the uPAR system as putative target for the development of novel drugs that may prevent type 2 DR.
Highlights
Diabetic retinopathy (DR) is a serious complication of diabetes that accounts for the large majority of cases of adult blindness in working age population
spontaneously diabetic Torii (SDT) rats are characterized by diabetic retinopathy (DR) that becomes established at about 20 weeks after diabetes onset and is followed by severe ocular complications including upregulated expression of vascular endothelial growth factor (VEGF), structural impairment of the neuroretina and gliosis, blood-retinal barrier leakage, and reduced electroretinogram (ERG) amplitude [5]
The goat polyclonal antibody directed to claudin-1, zonula occludens-1 (ZO-1; sc-8146), or FPR1, the rabbit polyclonal antibodies directed to claudin-5, glial fibrillary acidic protein (GFAP; sc-9065), uPAR, FPR2, FPR3, the p65 subunit of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB p65; sc-372), NF-κB p65 phosphorylated at Ser276 (pNF-κB (Ser276); sc-101749), or signal transducer and activator of transcription 3 (STAT3; sc-482), the mouse monoclonal antibody directed to STAT3 phosphorylated at Tyr705 (pSTAT3 (Tyr705); sc-8059), and the mouse antirabbit and the rabbit anti-goat horseradish peroxidaselabeled secondary antibodies were purchased from Santa Cruz Biotechnologies (Santa Cruz, CA, USA)
Summary
Diabetic retinopathy (DR) is a serious complication of diabetes that accounts for the large majority of cases of adult blindness in working age population. In type 1 diabetes, its early onset allows a precocious detection of the disease permitting a better control of DR, whereas, in type 2 diabetes, the late onset of DR delays its therapeutical treatments that are usually given when the disease has become vision-threating and are not always successful in restoring vision loss. The streptozotocin- (STZ-) induced rodent model is an acknowledged model of type 1 diabetes in which DR is established early after diabetes onset, and its features resemble. Male SDT rats spontaneously develop hyperglycemia after 20 weeks of age, becoming diabetic without obesity [4]. SDT rats are characterized by DR that becomes established at about 20 weeks after diabetes onset and is followed by severe ocular complications including upregulated expression of vascular endothelial growth factor (VEGF), structural impairment of the neuroretina and gliosis, blood-retinal barrier leakage, and reduced electroretinogram (ERG) amplitude [5]
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