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Hiroto Shibuki, Naomichi Katai, Sachiko Kuroiwa, Toru Kurokawa, Jun Arai, Kunio Matsumoto, Toshikazu Nakamura, Nagahisa Yoshimura; Expression and Neuroprotective Effect of Hepatocyte Growth Factor in Retinal Ischemia–Reperfusion Injury. Invest. Ophthalmol. Vis. Sci. 2002;43(2):528-536.
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purpose. To investigate the expression and possible neuroprotective effects of
hepatocyte growth factor (HGF) in a rat model of retinal
methods. Retinal ischemia was induced in adult male Sprague-Dawley rats by
raising the intraocular pressure to 110 mm Hg for 45 minutes. To study
expression of HGF and its receptor c-Met, reverse
transcription–polymerase chain reaction (RT-PCR), Western blot
analysis, and immunohistochemical staining were performed on eyes
enucleated at 6, 12, 24, 48, and 96 hours after reperfusion. To examine
the neuroprotective effects of HGF, recombinant human (rh)HGF (1, 6,
and 12 μg in 2 μL PBS) or vehicle was administered intravitreally 1
minute after reperfusion, and the eyes were enucleated at 6, 12, 24,
48, and 96 hours and 28 days after reperfusion. The retinal damage was
assessed by electroretinogram (ERG) recordings, by measuring the inner
retinal thickness, and by counting the number of TUNEL-positive cells
in each retinal layer.
results. RT-PCR and Western blot analyses showed upregulation of HGF and
c-Met–HGF receptor mRNA at 6, 12, 24, and 48 hours after reperfusion,
compared with the normal rat retina. Immunohistochemically, expression
of HGF was found in the retinal pigment epithelial cells at 6 hours
after reperfusion and in some cells in the ganglion cell layer and
inner nuclear layer at 24 hours after reperfusion. The amplitudes of
the ERG b-wave and oscillatory potentials were significantly larger in
the eyes treated with 6 and 12 μg rhHGF than in those of
vehicle-treated control rats (P < 0.01). On day
28, the thicknesses of the inner retina of vehicle-treated rats and
that of 6-μg rhHGF-treated rats were 54.4 ± 6.12 (mean ±
SD, n = 9) and 71.5 ± 9.81 μm (n= 8), respectively (P < 0.01). The number
of TUNEL-positive cells at 6, 12, 24, and 48 hours after reperfusion
was decreased significantly by treatment with 6 μg rhHGF, compared
with those in the control rats (P < 0.01).
conclusions. Upregulation of HGF in the retina may play a role in retinal
ischemia–reperfusion injury. Intravitreal injection of rhHGF is
neuroprotective against the injury.
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