Lens epithelium-derived growth factor promotes photoreceptor survival in light-damaged and RCS rats.
OBJECTIVE
To investigate possible protective effects of lens epithelium-derived growth factor (LEDGF) against photoreceptor death in light-damaged, Royal College of Surgeons (RCS) and P23H rhodopsin transgenic rats.


METHODS
Twelve-week-old Sprague-Dawley (SD), 6-week-old RCS, and 10-day-old P23H (line 1, heterozygote) rats received an intravitreal injection of LEDGF fused with glutathione-S-transferase (GST-LEDGF). Fellow eyes received vehicle and served as control specimens. Two days after the injections, the SD rats were exposed to light of 2000 lux for 48 hours. Corneal Ganzfeld ERGs were recorded 10 days after light damage, at 10 weeks of age in RCS rats, and at 4 weeks of age in P23H rats. The eyes were then processed for histologic analysis. Heat shock protein (hsp) content in the sensory retina was analyzed quantitatively by protein immunoblot.


RESULTS
In light-damaged rats, the ERG indicated retinal protection in GST-LEDGF-injected eyes, with b-wave and STR thresholds being 1.14 +/- 0.50 (mean +/- SD) and 0.60 +/- 0.26 log candela (cd)/m2 lower, respectively, than in vehicle-injected eyes (P < 0.01). The GST-LEDGF-treated eyes had maximum b-wave amplitudes that were significantly larger (P < 0.0005), had more than twice as many remaining photoreceptors, and had better organized outer segments than the control eyes. In RCS rats, the treated eyes had 2.76 +/- 0.73 and 0.83 +/- 0.09 log cd/m(2) lower thresholds for the b-wave and STR, respectively (P < 0.005), and had significantly larger maximum b-wave amplitude (P < 0.0005). GST-LEDGF-treated eyes of RCS rats also had more photoreceptors remaining (P < 0.005) and a thinner debris layer than control eyes. In P23H rats, GST-LEDGF treatment did not protect either retinal function or structure. The retinas from GST-LEDGF-treated eyes of SD and RCS rats had higher levels of hsp25 and alphaB-crystallin than vehicle-injected eyes.


CONCLUSIONS
GST-LEDGF protects photoreceptor structure and function in both light-damaged and RCS rats. The increased expression of hsp25 and alphaB-crystallin may play a role in this protection. The absence of rescue in P23H raises the possibility that some forms of inherited retinal degeneration may not be amenable to treatment by intraocular injection of LEDGF.
Kellogg Eye Center, University of Michigan, Ann Arbor 48105, USA.
S
S
Machida
P
P
Chaudhry
T
T
Shinohara
D P
DP
Singh
V N
VN
Reddy
L T
LT
Chylack
P A
PA
Sieving
R A
RA
Bush
D000818:Animals; D030801:Animals, Genetically Modified; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D004596:Electroretinography; D006133:Growth Substances / Q000494:pharmacology*; D006360:Heat-Shock Proteins / Q000378:metabolism; D015151:Immunoblotting; D007267:Injections; D036341:Intercellular Signaling Peptides and Proteins; D008027:Light / Q000009:adverse effects*; D008297:Male; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D011833:Radiation Injuries, Experimental / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins; D012162:Retinal Degeneration / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*
D006133:Growth Substances; D006360:Heat-Shock Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011993:Recombinant Fusion Proteins; C119380:lens epithelium-derived growth factor