Protective Effects of Bestatin in the Retina of Streptozotocin-induced Diabetic Mice.

Funding Source

National Institute on Minority Health and Health Disparities, National Science Foundation, U.S. Department of Health and Human Services, National Institutes of Health, U.S. Department of Defense

Grant Number

1503226, W911NF1510059


Department of Biology

Document Type


Publication Date



CD13/APN (aminopeptidase N) was first identified as a selective angiogenic marker expressed in tumor vasculature and is considered a target for anti-cancer therapy. CD13 was also reported to express in non-diabetic, hypoxia-induced retinal neovascularization. Whether diabetes induces upregulation of CD13 expression in the retina is unknown. We hypothesize that at an early stage of non-proliferative diabetic retinopathy (NPDR) characterized by disruption of blood-retinal barrier (BRB) permeability is related to upregulated expression of CD13 because of its known role in extracellular matrix (ECM) degradation. The purpose of this study is to evaluate the role of CD13/APN and the therapeutic efficacy of a CD13/APN inhibitor in a mouse model of streptozotocin-induced NPDR. Hyperglycemic C57Bl/6 mice 26 weeks after streptozotocin (STZ) injection were intravitreally injected with a sustained release formulation of CD13/APN inhibitor bestatin. At 15th day of post-bestatin treatment, mouse retinas were evaluated for vascular permeability by Evans blue dye extravasation assay, fluorescent angiography of retinal vascular permeability and leukostasis. Retinal protein extracts were analyzed by Western blot to determine the effects of bestatin treatment on the expression of CD13/APN related inflammatory mediators of ECM degradation and angiogenesis. Intravitreal bestatin treatment significantly inhibited retinal vascular permeability and leukostasis. This treatment also significantly inhibited retinal expression of CD13, ECM degrading proteases (heparanase and MMP9 and angiogenic molecules (HIF-1α and VEGF). Intravitreal CD13 inhibition may relate to furthering our knowledge on the protective effect of bestatin against diabetic retinal vasculature abnormalities through inhibition of retinal permeability, leukostasis, inflammatory molecules of ECM degradation and angiogenesis.


DOI: 10.1016/j.exer.2016.06.016

PubMed ID: 27344955

Funding text

Support is provided in part by grant number 2G12MD007595-06 (PSB) from the National Institute on Minority Health and Health Disparities (NIMHD) , National Institutes of Health (NIH) , Department of Health and Human Services (DHHS) , Department of Defense (DoD) grant # W911NF1510059 (TH, PSB), Louis Stokes Louisiana Alliance for Minority Participation (LS-LAMP) – National Science Foundation (NSF) human resource development (HRD) award # 1503226 (SM). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, NIGMS, NSF or DoD. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.