The Potential Role of Small-Molecule PERK Inhibitor LDN-0060609 in Primary Open-Angle Glaucoma Treatment

International Journal of Molecular Sciences

Natalia Siwecka¹  Ireneusz Majsterek¹  Dariusz Pytel¹  Wioletta Rozpędek-Kamińska¹  Grzegorz Galita¹  Ewa Kucharska²  StevenL. Carroll³  JohnAlan Diehl⁴ 

[1] Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, 90-419 Lodz, Poland;Department of Gerontology, Geriatrics and Social Work, Jesuit University Ignatianum, 31-501 Krakow, Poland;Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA;Hollings Cancer Center, Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA;

关键词: glaucoma;    PERK;    eIF2α;    endoplasmic reticulum stress;    unfolded protein response;    apoptosis;   

DOI  :  10.3390/ijms22094494

来源: DOAJ

【 摘 要 】

Primary open-angle glaucoma (POAG) constitutes the most common type of glaucoma. Emerging evidence suggests that Endoplasmic Reticulum (ER) stress and the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-mediated Unfolded Protein Response (UPR) signaling pathway play a key role in POAG pathogenesis. Thus, the main aim of the study was to evaluate the effectiveness of the PERK inhibitor LDN-0060609 in cellular model of glaucoma using primary human trabecular meshwork (HTM) cells. To evaluate the level of the ER stress marker proteins, Western blotting and TaqMan gene expression assay were used. The cytotoxicity was measured by XTT, LDH assays and Giemsa staining, whereas genotoxicity via comet assay. Changes in cell morphology were assessed by phase-contrast microscopy. Analysis of apoptosis was performed by caspase-3 assay and flow cytometry (FC), whereas cell cycle progression by FC. The results obtained have demonstrated that LDN-0060609 triggered a significant decrease of ER stress marker proteins within HTM cells with induced ER stress conditions. Moreover, LDN-0060609 effectively increased viability, reduced DNA damage, increased proliferation, restored normal morphology, reduced apoptosis and restored normal cell cycle distribution of HTM cells with induced ER stress conditions. Thereby, PERK inhibitors, such as LDN-0060609, may provide an innovative, ground-breaking treatment strategy against POAG.

【 授权许可】

Unknown