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Melissa A Calton, Jeffrey A Ma, Eric Chang, Jeffrey Litt, Stephanie S Chang, M. Angels Estiarte, Timothy P Shiau, Anirban Datta, David B Kita; An orally dosed plasma kallikrein inhibitor decreases retinal vascular permeability in a rat model of diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3576.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetic retinopathy (DR) is a leading cause of blindness in diabetic adults. In DR, the plasma kallikrein-kinin system is activated, thereby contributing to retinal vascular dysfunction and causing blood fluids to leak. We report efficacious intervention by reducing retinal leakage in orally dosed rats with diabetes-induced retinal vascular permeability.
Diabetes (blood glucose >300 mg/dL) was induced in 8-week old male Brown Norway rats upon streptozotocin treatment (65 mg/kg). After 14 days, diabetic (DM) and non-diabetic (NDM) rats were treated orally with vehicle or the plasma kallikrein inhibitor VE-3539 (25 mg/kg) once daily for 14 days. Retinal vascular permeability was examined by fluorescein angiography and quantified computationally by calculating image gradient strength normalized by the average intensity to yield a scaled gradient strength. Higher scaled gradient strength in this analysis equates to less observed retinal vascular permeability. Mean Circulation Time (MCT) was used as an index of flow between a retinal artery and vein. Multiple group comparisons for statistical significance were performed using Bonferroni correction for one-way ANOVA. Results are expressed as mean ±SD.
After 14 days of oral dosing, DM rats treated with VE-3539 had significantly higher scaled gradient strength (42.93 ±7.02; n=13), corresponding to lower leakage, compared to vehicle treated DM rats (30.24 ±8.10; n=11; p=0.002). No effect was found in NDM rats when treated with VE-3539 (60.34±11.97; n=6) vs. when treated with vehicle (55.20±6.23; n=6). Further, MCT was significantly shorter in VE-3539 (1.18±0.18 sec) vs. vehicle treated DM rats (1.56±0.20 sec; p<0.0001).
Our results demonstrate that inhibition of the activated plasma kallikrein-kinin system with a potent plasma kallikrein inhibitor can decrease retinal blood vessel leakage. Orally dosing DM rats significantly decreases retinal vascular permeability and decreases MCT.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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