Diabetic Retinopathy in the Spontaneously Diabetic Torii Rat: Pathogenetic Mechanisms and Preventive Efficacy of Inhibiting the Urokinase-Type Plasminogen Activator Receptor System

The Spontaneoulsly diabetic Torii (SDT) rat is of increasing preclinical interest because of its long-lasting pathophysiological similarities to human type 2 diabetic retinopathy (DR). The system formed by urokinase-type plasminogen activator (uPA) and its receptor (uPAR) is a major player in blood retinal barrier (BRB) breakdown in DR. Here, we investigated whether in SDT rats preventive long-lasting 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 real-time PCR, ELISA, Evans blue perfusion and Western blot were also used to evaluate UPARANT efficacy. UPARANT prevented ERG dysfunction, upregulated expression of vascular endothelial growth factor (VEGF) and fibroblobast growth factor-2 (FGF-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 curative short-lasting administration of UPARANT is known to efficiently inhibits 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 either 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.