Involvement of c-Jun N-terminus kinase 2 (JNK2) in Endothelin-1 (ET-1) mediated neurodegeneration of retinal ganglion cells

Abstract Purpose The goal of this study was to determine if JNK2 plays a causative role in endothelin-mediated loss of RGCs in mice. Methods JNK2 -/- and wild type (C57BL/6) mice were intravitreally injected in one eye with 1 nmole of ET-1, while the contralateral eye was injected with the vehicle. At two time points (2 h and 24 h) following the intravitreal injections, retinal sections were obtained and phosphorylated c-Jun was assessed. In a separate set of experiments, JNK2 -/- and wild type mice were intravitreally injected with either 1 nmole of ET-1 or its vehicle, and euthanized 7 days post-injection. Retinal flat mounts were stained with antibodies to the RGC marker, Brn3a, and surviving RGCs were quantified. Axonal degeneration was assessed by imaging PPD stained optic nerve sections. Results Intravitreal ET-1 administration produced a significant increase in immunostaining for phospho c-Jun in wild type mice, which was appreciably lower in the JNK2 -/- mice. A significant (p<0.05) 26% loss of RGCs was found in wild type mice, 7 days post injection with ET-1. JNK2 -/- mice showed a significant (p=0.36) protection from RGC loss following ET-1 administration, compared to wild type mice injected with ET-1. A significant decrease in axonal counts and an increase in the collapsed axons was found in ET-1 injected mice eyes. Conclusion JNK2 appears to play a major role in ET-1 mediated loss of RGCs in mice. Neuroprotective effects of JNK2 following ET-1 administration occur mainly in the soma and not in the axons of RGCs.