Neuroprotective Effect of Upregulated Sonic Hedgehog in Retinal Ganglion Cells Following Chronic Ocular Hypertension

PURPOSE. To determine sonic hedgehog (Shh) expression and whether it exerts neuroprotective effects on retinal ganglion cells (RGCs) in a rat chronic ocular hypertension model. METHODS. Intraocular pressure (IOP) elevation in adult rat was induced by episcleral vein cautery. Retinal expression of Shh protein and mRNA was determined by immunohistochemistry, Western blot analysis, and real-time PCR. Exogenous Shh and its inhibitor cyclopamine were intravitreally injected to examine their effects on RGC survival after ocular hypertension by the counting of retrograde DiI-labeled RGCs. Shh pathway components mediating neuroprotective effects were characterized using Western blot analysis and real-time PCR. RESULTS. Shh was mainly detected in the RGCs in normal adult rat. Retinas from the elevated IOP group had 2.1- to 4.4-fold greater Shh expression than control retinas (P < 0.05). Shh promoted RGC survival at 2 and 4 weeks after IOP elevation in a dose-dependent manner, resulting in a loss of only 4.54% +/- 0.36% RGCs at 2 weeks (P < 0.01; vs. PBS-treated groups). In contrast, cyclopamine increased RGC loss. Protein and mRNA levels of the Shh signal transducer Smo and the downstream transcription factor Gli1 were significantly upregulated in RGCs after chronic ocular hypertension or intravitreal injection of Shh. CONCLUSIONS. Shh and Smo are upregulated in a time-dependent manner in retinas exposed to ocular hypertension, and Shh has neuroprotective effects on damaged RGCs in a rat chronic hypertension model. Shh may exert neuroprotective effects by relieving the inhibition of Smo and subsequently activating Gli1. (Invest Ophthalmol Vis Sci. 2010; 51: 2986-2992) DOI:10.1167/iovs.09-4151