Role of angiotensin II type 1 receptor on retinal vascular leakage in a rat oxygen-induced retinopathy model.
OBJECTIVE
To investigate the role of angiotensin type 1 (AT1) and type 2 (AT2) receptors in hypoxia-induced retinal vascular hyperpermeability.


METHODS
Brown-Norway rat pups were exposed to hyperoxic conditions from postnatal day 7 (P7) to P12, and to subsequent normal air for 5 days [oxygen-induced retinopathy (OIR) model]. Olmesartan medoxomil (AT1 receptor antagonist; administered orally), PD123319 (AT2 receptor antagonist; administered subcutaneously) or a vehicle was administered once daily during the last 5 days. At P16, the retinal permeability was determined by measuring the leaked fluorescein-conjugated dextran concentration in the retina. The vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1 (HIF-1) alpha proteins in the retina were assessed by an ELISA and western blotting, respectively.


RESULTS
Olmesartan medoxomil partially, but significantly, inhibited the retinal vascular hyperpermeability induced by hypoxia. In contrast, PD123319 did not show a significant effect. The VEGF and HIF-1alpha protein levels were significantly elevated in the OIR retina; however, there was no significant effect of olmesartan medoxomil on the expression of either protein.


CONCLUSIONS
These results suggest that the AT1 receptor is, at least partly, responsible for hyperpermeability in the OIR rat retina via a mechanism independent of HIF-1 and VEGF expression.
Nakamura
Hiroaki
H
Biological Research Laboratories II, R&D Division, Daiichi-Sankyo Co., Ltd., Tokyo, Japan. nakamura.hiroaki.xn@daiichisankyo.co.jp
Yamazaki
Mami
M
Ohyama
Takao
T
Inoue
Tatsuya
T
Arakawa
Naohisa
N
Domon
Yuki
Y
Yokoyama
Tomihisa
T
D000284:Administration, Oral; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D051793:Hypoxia-Inducible Factor 1 / Q000096:biosynthesis; D007093:Imidazoles / Q000008:administration & dosage; D007279:Injections, Subcutaneous; D007511:Ischemia; D000068557:Olmesartan Medoxomil; D010100:Oxygen / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*; D044139:Receptor, Angiotensin, Type 2 / Q000502:physiology; D012164:Retinal Diseases / Q000378:metabolism* / Q000473:pathology; D012171:Retinal Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D013777:Tetrazoles / Q000008:administration & dosage; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D014662:Vasoconstrictor Agents / Q000008:administration & dosage
D047228:Angiotensin II Type 1 Receptor Blockers; D051793:Hypoxia-Inducible Factor 1; D007093:Imidazoles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D042461:Vascular Endothelial Growth Factor A; D014662:Vasoconstrictor Agents; C073402:PD 123319; D000068557:Olmesartan Medoxomil; D010100:Oxygen