iridoids and Diabetic-Retinopathy

Geniposide (GEN) is a natural antioxidant and anti-inflammatory product and plays an important role in the treatment of diabetes and diabetic complications. To explore the biological functions and mechanism of GEN in diabetic retinopathy (DR), we constructed the in vitro and in vivo model of DR by using primary cultured mouse retinal Müller cells and C57BL/6 mice, respectively. We found that GEN inhibited ROS accumulation, NF-

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Ependymoglial Cells; Hyperglycemia; Inflammation; Iridoids; Male; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Oxidative Stress; Reactive Oxygen Species

We address the hypothesis that uncoupling protein 2 (UCP2), a cellular glucose regulator, delays physiologic retinal vascular development (PRVD) by interfering with glucose uptake through glucose transporter 1 (Glut1).. In the rat 50/10 oxygen-induced retinopathy (OIR) model, retinal Glut1 and UCP2 were measured and compared to room air (RA)-raised pups at postnatal day 14 (p14). Pups in OIR and RA received intraperitoneal genipin, an UCP2 inhibitor, or control every other day from p3 until p13. Analyses at p14 included avascular/total retinal area (AVA), Western blots of retinal UCP2 and Glut1, and immunostaining of Glut1 in retinal cryosections. Intravitreal neovascular/total retinal area (IVNV) was analyzed at p18, and electroretinograms were performed at p26. Glut1 and phosphorylated VEGFR2 (p-VEGFR2), glucose uptake, adenosine triphosphate (ATP) production, and cell proliferation were measured in human retinal microvascular endothelial cells (hRMVECs) pretreated with genipin or transfected with UCP2siRNA, Glut1siRNA, or control siRNA when incubated with VEGF or PBS.. At p14, OIR pups had increased AVA with decreased Glut1 and increased UCP2 in the retina compared to RA retinas. Intraperitoneal genipin increased retinal Glut1 and reduced AVA. Compared to control, treatment with genipin or knockdown of UCP2 significantly increased Glut1, glucose uptake, ATP production, VEGF-induced p-VEGFR2 and cell proliferation in hRMVECs. Knockdown of Glut1 inhibited VEGF-induced p-VEGFR2. Genipin-treated OIR pups with decreased AVA at p14 had reduced IVNV at p18 and increased amplitudes in a- and b-waves at p26.. Extending PRVD by increasing retinal endothelial glucose uptake may represent a strategy to prevent severe retinopathy of prematurity and vision loss.

Topics: Adenosine Triphosphate; Animals; Animals, Newborn; Blotting, Western; Cholagogues and Choleretics; Diabetic Retinopathy; Disease Models, Animal; Electroretinography; Endothelium, Vascular; Female; Gene Silencing; Glucose; Glucose Transporter Type 1; Glycolysis; Injections, Intraperitoneal; Iridoids; Male; Oxygen; Pregnancy; Rats; Rats, Sprague-Dawley; Retinal Vessels; Transfection; Uncoupling Protein 2; Vascular Endothelial Growth Factor Receptor-2