The Urokinase Receptor-Derived Peptide UPARANT as a novel therapy to recover high glucose-associated retinal damage in spontaneously diabetic Torii rats

Abstract

Purpose : Spontaneously diabetic Torii (SDT) rats are an inbred strain of rats with a non-obese type 2 diabetes mellitus that were isolated from an outbred colony of Sprague–Dawley (SD) rats. They develop diabetes mellitus at about 20 weeks of age and, about 24 weeks later, are characterized by alterations of electroretinogram (ERG) and blood retinal barrier (BRB) dysfunction followed by later proliferative neovascularization. SDT rats are a useful model to investigate possible therapeutical approaches that may counteract the pathological signs of diabetic retinopathy (DR). The urokinase-type plasminogen activator (uPA)/uPA receptor (uPAR) system is up-regulated in rat models of DR and treatments downregulating this system may have some effects. We tested the possibility that systemic administration of UPARANT, a highly resistant peptide inhibitor of the uPA/uPAR system, might prevent visual dysfunction and BRB leakage in SDT rats.

Methods : SDT rats without or with UPARANT treatment^. were used. SD rats were also used as non diabetic controls. Treatment started at 7 weeks after diabetes onset and included the subcutaneous administration of UPARANT at 10 mg/kg once a week or 7 mg/kg 3 times a week. ERG was recorded either before treatment or every 2 weeks over treatment duration. Rats were dark-adapted overnight and single-flash ERG was recorded at an intensity of -3,4 to 1 log cd-s/m². At 40 weeks after diabetes onset, SDT rats, either treated or untreated, were transcardially perfused with Evans blue dye and BRB was evaluated qualitatively on fresh flat mounted retinas with a fluorescence microscope.

Results : SDT rats either untreated or treated with UPARANT at 10 mg/kg once a week displayed significantly reduced amplitude of the a- and b-waves and marked BRB leakage. In contrast, SDT rats treated with UPARANT at 7 mg/kg 3 times a week displayed functional ERG and unaltered BRB without any significant difference with non diabetic control SD rats.

Conclusions : Our results demonstrate that UPARANT effectively prevents the onset of DR thus presumably interfering with late neovascularization processes. The present data support the hypothesis that systemic UPARANT may represent the basis for the development of novel uPAR-targeting approaches for DR therapy.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.