Pathways Responsible for Apoptosis Resulting from Amadori-Induced Oxidative and Nitrosative Stress in Human Mesothelial Cells

• Published in: American journal of nephrology Vol. 34; no. 2; pp. 104 - 114
• Main Authors: Sánchez-Rodríguez, Carolina, Peiró, Concepción, Vallejo, Susana, Matesanz, Nuria, El-Assar, Mariam, Azcutia, Verónica, Romacho, Tania, Sánchez-Ferrer, Carlos Félix, Rodríguez-Mañas, Leocadio, Nevado, Julián
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland S. Karger AG 01.01.2011
• Subjects: Animals; Apoptosis; Cattle; Cell Death; Cytochromes c - metabolism; Epithelium - pathology; Glycolipids - pharmacology; Humans; Hyperglycemia - metabolism; Inflammation; L-Lactate Dehydrogenase - metabolism; MAP Kinase Signaling System; Nitrogen - metabolism; Original Report: Laboratory Investigation; Oxidative Stress; Phosphatidylethanolamines - pharmacology; Proto-Oncogene Proteins c-jun - metabolism; Signal Transduction; Amadori adducts; Reactive oxygen species; Caspases; Human mesothelial cells; Apoptosis; Mitogen-activated protein kinases
• ISSN: 0250-8095; 1421-9670
• DOI: 10.1159/000329107

Background: Apoptosis and inflammatory/oxidative stress have been associated with hyperglycemia in human peritoneal mesothelial cells (HPMCs) and other cell types. We and others have highlighted the role of early products of non-enzymatic protein glycation in inducing proinflammatory conditions and increasing apoptotic rates in HPMCs. Loss of HPMCs seems to be a hallmark of complications associated with peritoneal membrane dysfunction. The aim of this work is to elucidate the mechanisms by which Amadori adducts may act upon HPMC apoptosis. Methods: HPMCs isolated from different patients were exposed to different Amadori adducts, i.e. highly glycated hemoglobin (10 nM) and glycated bovine serum albumin (250 µg/ml), to study cell death and several proapoptotic markers by different experimental approaches. Results: Amadori adducts, but not their respective controls, impaired cell proliferation and cell viability by means of apoptosis in a time-dependent manner. They regulated the intrinsic mitochondrial cell death signaling pathway and modulated activation of caspases, Bax, iNOS, p53, NF-ĸB, and mitogen-activated protein kinases (p38 and JNK) through different reactive oxygen and nitrosative species. Conclusions: Our data strongly support the idea that long-term hyperglycemia could act as an inducer of apoptosis in HPMCs through Amadori adducts, involving different oxidative and nitrosative reactive species.