Reduced expression of active neuroprotective kinases in the glaucomatous compared to the healthy aging retina

Abstract

Purpose : In preclinical models of glaucoma, protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) pathways have been targeted pharmacologically to alter kinase phosphorylation for therapeutic benefit. Here, we report changes in the levels of active, phosphorylated forms of Akt and ERK in the retina of the DBA/2J mouse, a model of chronic age-related pigmentary glaucoma, as dependent on disease severity and different from healthy controls.

Methods : Levels of immunoreactivity for ERK1/2 and Akt and their activated phosphorylated forms (pERK1/2: phosphorylated at Thr²⁰²/Tyr²⁰⁴; pAkt: phosphorylated at Thr³⁰⁸/Ser⁴⁷³) in the retinae of male 1.5 and 9 month-old DBA/2J and C57BL/6 mice were determined using immunoblotting and correlated with intraocular pressure (IOP), visual acuity and contrast sensitivity.

Results : Levels of pERK1 and pERK2 were 10.0 (p<0.001) and 25.8 (p<0.05) fold higher in 1.5 month-old and 3.7 (p<0.001) and 9.6 (p<0.01) fold higher in 9 month-old C57BL/6 mice when compared to age-matched DBA/2J mice. pERK/ERK ratios increased significantly during glaucoma disease progression (from 1.5 to 9 months) in DBA/2J mice by 2.4 fold (pERK1; p<0.05) and 1.8 fold (pERK2; p<0.05), however, remained the same during normal ageing in C57BL/6 mice. Retinal pAkt levels were 1.7 (p<0.05) and 4.3 (p<0.001) fold higher in 1.5 and 9 month-old C57BL/6 mice, respectively, compared to age-matched DBA/2J mice. pAkt/Akt ratios increased significantly (1.65 fold; p<0.05) during normal ageing (from 1.5 to 9 months) in C57BL/6 mice, however, remained the same over time during glaucoma disease progression in DBA/2J mice. Levels of pERK1/2 and pERK/ERK ratios showed a strong correlation with IOP and contrast sensitivity and a moderate correlation with visual acuity in DBA/2J mice, but not in C57BL/6 mice. pAkt levels and pAkt/Akt ratios were correlated moderately with IOP, strongly with visual acuity, and not correlated with contrast sensitivity.

Conclusions : Altered levels of active ERK1/2 and Akt with ageing and with progression of glaucoma correlate with glaucoma disease progression and disease-related vision loss. Therefore, attenuated ERK and Akt signaling is a potential mechanism contributing to glaucoma pathogenesis in the retina and represent druggable targets.

This is a 2020 ARVO Annual Meeting abstract.