Year: 2015
Type: article
Abstract: Diabetic retinopathy (DR) is a leading cause of blindness worldwide, and its prevalence is growing. Current therapies for DR address only the later stages of the disease, are invasive, and have limited effectiveness. Retinal pericyte death is an early pathologic feature of DR. Although it has been observed in diabetic patients and in animal models of DR, the cause of pericyte death remains unknown. A novel pro-apoptotic pathway initiated by the interaction between glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the E3 ubiquitin ligase, seven in absentia homolog 1 (Siah1), was recently identified in ocular tissues. In this article we examined the involvement of the GAPDH/Siah1 interaction in human retinal pericyte (hRP) apoptosis. HRP were cultured in 5 mm normal glucose, 25 mm l- or d-glucose for 48 h (osmotic control and high glucose treatments, respectively). Siah1 siRNA was used to down-regulate Siah1 expression. TAT-FLAG GAPDH and/or Siah1-directed peptides were used to block GAPDH and Siah1 interaction. Co-immunoprecipitation assays were conducted to analyze the effect of high glucose on the association of GAPDH and Siah1. Apoptosis was measured by Annexin V staining and caspase-3 enzymatic activity assay. High glucose increased Siah1 total protein levels, induced the association between GAPDH and Siah1, and led to GAPDH nuclear translocation. Our findings demonstrate that dissociation of the GAPDH/Siah1 pro-apoptotic complex can block high glucose-induced pericyte apoptosis, widely considered a hallmark feature of DR. Thus, the work presented in this article can provide a foundation to identify novel targets for early treatment of DR.
Source: Journal of Biological Chemistry
Authors: Sandra Suarez, Gary W. McCollum, Ashwath Jayagopal, John S. Penn
Language: English
Subfield: Ophthalmology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Awards: G1005759312, G1698461174, The Vanderbilt Institute for Clinical and Translational Research (VICTR), The calcineurin/NFAT signaling axis in diabetic retinopathy pathogenesis, G2537422520, LSM880-Airyscan Confocal Microscope for Large Shared Resource, G4790680440, Initiative for Maximizing Student Development, Molecular Mechanisms of Retinal Vascular Disease, The Vanderbilt Institute for Clinical and Translational Research (VICTR), G5991419914, The Vanderbilt Institute for Clinical and Translational Research (VICTR), G9000173433, Core Grant in Vision Research
OpenAlex ID: W2285733306