Plasminogen kringle 5 reduces vascular leakage in the retina in rat models of oxygen-induced retinopathy and diabetes.
OBJECTIVE
Retinal vascular leakage is an early pathological feature in diabetic retinopathy and can lead to macular oedema and loss of vision. Previously we have shown that plasminogen kringle 5 (K5), an angiogenic inhibitor, inhibits retinal neovascularisation in the rat model of oxygen-induced retinopathy (OIR). The purpose of this study was to examine the effect of K5 on vascular leakage in the retina.


METHODS
Neonatal rats were exposed to hyperoxia to induce OIR. Diabetes was induced in adult rats by injecting streptozotocin. Vascular permeability was measured by Evans blue method. Expression of vascular endothelial growth factor (VEGF) was evaluated using immunohistochemistry and western blot analysis.


RESULTS
Rats with OIR and diabetes showed abnormal vascular hyperpermeability in the retina and iris. Intravitreal injection of K5, reduced vascular permeability in both animal models, but did not affect permeability in normal rats. K5 reduced vascular permeability at doses substantially lower than that required for inhibition of retinal neovascularisation. The K5-induced reduction in vascular permeability correlated with its down-regulation of VEGF expression in the retina. Moreover, K5 inhibited IGF-1-induced hyperpermeability, which is known to arise through up-regulation of endogenous VEGF expression. However, K5 had no effect on the hyperpermeability induced by injection of exogenous VEGF.


CONCLUSIONS
Very low doses of K5 reduce pathological vascular leakage in the retina. K5 thus has therapeutic potential in the treatment of diabetic macular oedema. This effect can be ascribed, at least in part, to the down-regulation of endogenous VEGF expression.
Zhang
S X
SX
Department of Medicine, The University of Oklahoma Health Science Center, 941 Stanton L. Young Blvd., BSEB 328B, Oklahoma City, OK 73104-5043, USA.
Sima
J
J
Shao
C
C
Fant
J
J
Chen
Y
Y
Rohrer
B
B
Gao
G
G
Ma
J-x
JX
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology*; D003930:Diabetic Retinopathy / Q000473:pathology / Q000517:prevention & control*; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D010446:Peptide Fragments / Q000627:therapeutic use*; D010958:Plasminogen / Q000627:therapeutic use*; D051381:Rats; D011914:Rats, Inbred BN; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D010446:Peptide Fragments; D042461:Vascular Endothelial Growth Factor A; C491499:plasminogen kringle 5; D007334:Insulin-Like Growth Factor I; D010958:Plasminogen