Leukostasis and pigment epithelium-derived factor in rat models of diabetic retinopathy.
OBJECTIVE
Spontaneously diabetic Torii (SDT) rats, an animal model of type 2 diabetes, have a low incidence of neovascular formation and an absence of non-perfused areas in their retinas at the proliferative stage that presents tractional retinal detachment with fibrous proliferation. The aim of this study was to determine whether leukostasis is present in the retina, to evaluate the levels of pigment epithelium-derived factor (PEDF) and intracellular adhesion molecule-1 (ICAM-1) levels in the blood of SDT rats, and to examine the effects of PEDF on leukostasis.


METHODS
SDT rats, streptozotocin-induced diabetic (STZ) rats, and control Sprague-Dawley (SD) rats were studied. The index of leukostasis in the retina was determined immunohistochemically by counting the number of labeled adherent leukocytes. The levels of PEDF and the soluble intracellular adhesion molecule (sICAM)-1 in the plasma were measured. To investigate the effect of PEDF and vascular endothelial growth factor (VEGF) on leukostasis, the adhesion of monocytes to human umbilical vein endothelial cells (HUVECs) was assayed in vitro.


RESULTS
SDT and STZ diabetic rats showed a significant increase of retinal leukostasis compared to that of control SD rats, but SDT rats had noteworthy lower levels of leukostasis than STZ rats in long term experiments. The sICAM-1 levels and PEDF expression were up-regulated in both STZ and SDT rats, but the SDT rats showed significantly higher levels of PEDF than STZ rats. In vitro studies showed that exposure of HUVECs to VEGF increased the number of adhering monocytes, and PEDF inhibited the VEGF-induced leukostasis in a dose-dependent manner.


CONCLUSIONS
The inhibition of the VEGF-induced leukostasis by PEDF is most likely responsible for the low incidence of capillary occlusion and retinal neovascularization in SDT rats.
Matsuoka
Masato
M
Department of Ophthalmology, Kansai Medical University, Osaka, Japan.
Ogata
Nahoko
N
Minamino
Keizo
K
Matsumura
Miyo
M
D000818:Animals; D001769:Blood; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000378:metabolism* / Q000473:pathology*; D042783:Endothelial Cells / Q000502:physiology; D005136:Eye Proteins / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry / Q000378:metabolism; D018921:Leukostasis / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control; D009000:Monocytes / Q000502:physiology; D009414:Nerve Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D015843:Serpins / Q000378:metabolism* / Q000494:pharmacology; D012720:Severity of Illness Index; D012995:Solubility; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D000099174:Pigment Epithelium-Derived Factor
D005136:Eye Proteins; D018799:Intercellular Adhesion Molecule-1; D009414:Nerve Growth Factors; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor