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

Abstract

AbstractPurposeThe goal of this study was to determine if JNK2 plays a causative role in endothelin-mediated loss of RGCs in mice.MethodsJNK2-/- 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.ResultsIntravitreal 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.ConclusionJNK2 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.