2 research outputs found
Autophagy and KRT8/keratin 8 protect degeneration of retinal pigment epithelium under oxidative stress
<p>Contribution of autophagy and regulation of related proteins to the degeneration of retinal pigment epithelium (RPE) in age-related macular degeneration (AMD) remain unknown. We report that upregulation of KRT8 (keratin 8) as well as its phosphorylation are accompanied with autophagy and attenuated with the inhibition of autophagy in RPE cells under oxidative stress. KRT8 appears to have a dual role in RPE pathophysiology. While increased expression of KRT8 following autophagy provides a cytoprotective role in RPE, phosphorylation of KRT8 induces pathologic epithelial-mesenchymal transition (EMT) of RPE cells under oxidative stress, which is mediated by MAPK1/ERK2 (mitogen-activated protein kinase 1) and MAPK3/ERK1. Inhibition of autophagy further promotes EMT, which can be reversed by inhibition of MAPK. Thus, regulated enhancement of autophagy with concurrent increased expression of KRT8 and the inhibition of KRT8 phosphorylation serve to inhibit oxidative stress-induced EMT of RPE cells as well as to prevent cell death, suggesting that pharmacological manipulation of KRT8 upregulation through autophagy with combined inhibition of the MAPK1/3 pathway may be attractive therapeutic strategies for the treatment of AMD.</p
Exosomal Proteins in the Aqueous Humor as Novel Biomarkers in Patients with Neovascular Age-related Macular Degeneration
Age-related macular degeneration
(AMD) describes the progressive
degeneration of the retinal pigment epithelium (RPE), retina, and
choriocapillaris and is the leading cause of blindness in people over
50. The molecular mechanisms underlying this multifactorial disease
remain largely unknown. To uncover novel secretory biomarkers related
to the pathogenesis of AMD, we adopted an integrated approach to compare
the proteins identified in the conditioned medium (CM) of cultured
RPE cells and the exosomes derived from CM and from the aqueous humor
(AH) of AMD patients by LC–ESI–MS/MS. Finally, LC–MRM
was performed on the AH from patients and controls, which revealed
that cathepsin D, cytokeratin 8, and four other proteins increased
in the AH of AMD patients. The present study has identified potential
biomarkers and therapeutic targets for AMD treatment, such as proteins
related to the autophagy–lysosomal pathway and epithelial–mesenchymal
transition, and demonstrated a novel and effective approach to identifying
AMD-associated proteins that might be secreted by RPE in vivo in the
form of exosomes. The proteomics-based characterization of this multifactorial
disease could help to match a particular marker to particular target-based
therapy in AMD patients with various phenotypes