title: Amadori products promote cellular senescence activating insulin-like growth factor-1 receptor and down-regulating the antioxidant enzyme catalase.
abstract: Activation of the insulin growth factor receptor-1 signaling pathways has been largely related to the aging process. Amadori products are produced in pathological conditions such as diabetes and aging, and are potentially involved in diabetic nephropathy or age-associated decline of renal function. We hypothesize that Amadori products induce senescence in primary human mesangial cells through the activation of IGF-1 receptor and investigate, in the present work, the intracellular mechanism involved after this activation. We treated cultured human mesangial cells with glycated albumin, one of the most abundant Amadori product, and senescence was assessed by determining the senescence associated β-galactosidase activity and the expression of the cell cycle regulators p53 and p21. We demonstrated that prolonged exposition (more than 24h) to glycated albumin induced senescence and, in parallel, incremented the release of IGF-1 and the activation of the IGF-1 receptor. Inhibition of the IGF-1 activation prevented the GA induced senescence. Activation of IGF-1R, after GA addition, promoted a reduction in the catalase content through the constitutive activation of Ras and erk1/2 proteins which were, in turn, responsible of the observed GA-induced senescence. In conclusion, we propose that the Amadori product, glycated albumin, promotes premature cell senescence in mesangial cells through the activation of the IGF-1 receptor and the subsequent reduction in the antioxidant enzyme catalase.
authors.affiliation: Department of Physiology, University of Alcalá, Alcalá de Henares, Madrid 28871, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Del Nogal-Ávila
authors.forename: Nuria
authors.initials: N
authors.lastname: Troyano-Suárez
authors.forename: Pablo
authors.initials: P
authors.lastname: Román-García
authors.forename: Jorge B
authors.initials: JB
authors.lastname: Cannata-Andía
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodriguez-Puyol
authors.forename: Diego
authors.initials: D
authors.lastname: Rodriguez-Puyol
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuro-O
authors.forename: María P
authors.initials: MP
authors.lastname: Ruiz-Torres
mesh_terms: D002374:Catalase / Q000096:biosynthesis*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D015536:Down-Regulation; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism; D017127:Glycation End Products, Advanced; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D050527:Mesangial Cells / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D012709:Serum Albumin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D001616:beta-Galactosidase / Q000187:drug effects / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000096:biosynthesis; D000093423:Glycated Serum Albumin
chemical_list: D017127:Glycation End Products, Advanced; D012709:Serum Albumin; D016159:Tumor Suppressor Protein p53; D007334:Insulin-Like Growth Factor I; D002374:Catalase; D017526:Receptor, IGF Type 1; D001616:beta-Galactosidase; D020741:rho GTP-Binding Proteins; D000093423:Glycated Serum Albumin