title: Mild exposure of RIN-5F β-cells to human islet amyloid polypeptide aggregates upregulates antioxidant enzymes via NADPH oxidase-RAGE: an hormetic stimulus.
abstract: The presence of amyloid aggregates of human islet amyloid polypeptide (hIAPP), a hallmark of type 2 diabetes, contributes to pancreatic β-cell impairment, where oxidative stress plays a key role. A contribution of NADPH oxidase to reactive oxygen species (ROS) generation after cell exposure to micromolar concentrations of hIAPP aggregates has been suggested. However, little is known about β-cells exposure to lower amounts of hIAPP aggregates, similar to those found in human pancreas. Thus, we aimed to investigate the events resulting from RIN-5F cells exposure to nanomolar concentrations of toxic hIAPP aggregates. We found an early and transient rise of NADPH oxidase activity resulting from increased Nox1 expression following the engagement of receptor for advanced glycation end-products (RAGE) by hIAPP aggregates. Unexpectedly, NADPH oxidase activation was not accompanied by a significant ROS increase and the lipoperoxidation level was significantly reduced. Indeed, cell exposure to hIAPP aggregates affected the antioxidant defences, inducing a significant increase of the expression and activity of catalase and glutathione peroxidase. We conclude that exposure of pancreatic β-cells to nanomolar concentrations of hIAPP aggregates for a short time induces an hormetic response via the RAGE-Nox1 axis; the latter stimulates the enzymatic antioxidant defences that preserve the cells against oxidative stress damage.
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Borchi
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Bargelli
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Guidotti
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy ; Research Centre on the Molecular Basis of Neurodegeneration (CIMN), Viale Morgagni 50, 50134 Florence, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Berti
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy ; Research Centre on the Molecular Basis of Neurodegeneration (CIMN), Viale Morgagni 50, 50134 Florence, Italy ; National Institute of Biostructures and Biosystems (INBB), Viale Medaglie d'Oro 305, Rome, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Stefani
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Nediani
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Rigacci
mesh_terms: D000818:Animals; D002374:Catalase / Q000378:metabolism; D045744:Cell Line, Tumor; D005979:Glutathione Peroxidase / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D058228:Islet Amyloid Polypeptide / Q000494:pharmacology*; D015227:Lipid Peroxidation; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D058228:Islet Amyloid Polypeptide; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D019255:NADPH Oxidases
keywords: AGE, advanced glycation end products; ATZ, 3-amino-1,2,4-triazole; Antioxidant enzyme; CAT, catalase; DPI, diphenyleneiodonium; GPx, glutathione peroxidase; Hormesis; MDA, malonyldialdehyde; MS, mercaptosuccinic acid; NADPH oxidase; RAGE; RAGE, receptor for advanced glycation end-products; ROS, reactive oxygen species; SOD, superoxide dismutase; Type 2 diabetes; hIAPP; hIAPP, human islet amyloid polypeptide; rIAPP, rat islet amyloid polypeptide