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J. Wu, S. Zhang, X. Sun; Neuroprotective Effect of Up-regulated Sonic Hedgehog in Retinal Ganglion Cells Following Chronic Ocular Hypertension. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2758.
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To determine sonic hedgehog (Shh) expression and whether it exerts neuroprotective effects on RGCs in a rat chronic ocular hypertension model.
Intraocular pressure (IOP) elevation was induced in rats by episcleral veins cautery. Protein and mRNA expressions of Shh were determined by immunohistochemistry, western blotting and real-time PCR. Exogenous Shh and its inhibitor cyclopamine were injected intravitreally to examine their effects on RGC survival after ocular hypertension by the counting of retrograde Dil-labeled RGCs. Shh signal pathway mediating neuroprotective effects were characterized using Western blotting and real-time PCR.
IOP elevated-retinas showed a 2.1- to 4.4-fold increase in Shh expression, compared to the control eyes (p<0.05). Exogenous Shh significantly promotes RGC survival 2 and 4 weeks after ocular hypertension, whereas cyclopamine increased RGC loss. 15.26% ± 1.57% RGCs were lost 2 weeks after IOP elevation in the PBS-treatment groups. In contrast, Shh-treated retinas lost only 4.54% ± 0.36% of RGCs (P<0.01). The injected cyclopamine reduced the number of RGCs by ~70% in a dose-dependent manner compared with the vehicle control after ocular hypertension. Western blotting and real-time PCR revealed that Smo, a shh signal transducer, and transcription factor Gli1 were significantly up-regulated in RGCs following chronic ocular hypertension or Shh-intravitreal treatment. Ptc, a shh binding receptor, However, was not detectably up-regulated both in mRNA and protein expression.
Shh and its signal transducer Smo are up-regulated in a time-dependent manner in retinas exposed to ocular hypertension and that Shh, either endogenous or exogenous, has neuroprotective effects on damaged RGCs in a well-established rat model of chronic hypertension. Shh may exert neuroprotective effects by relieving the inhibition of Smo and subsequently activating transcriptional factor Gli1.
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