title: Advanced oxidation protein products promote NADPH oxidase-dependent β-cell destruction and dysfunction through the Bcl-2/Bax apoptotic pathway.
abstract: The accumulation of plasma advanced oxidation protein products (AOPPs) has been linked with diverse disorders, including diabetes, chronic kidney disease, obesity, and metabolic syndrome. The aim of the present study was to evaluate the pathophysiological relevance of AOPPs in β-cell destruction and dysfunction. Exposure of cultured rat β-cells (INS-1) to AOPPs induced an increase in Bax expression, caspase-3 activity, and apoptosis as well as a decrease in Bcl-2 expression in a dose- and time-dependent manner. AOPP challenge rapidly increased the production of intracellular superoxide by activation of NADPH oxidases, demonstrated by p47phoxtranslocation and interaction with p22phoxand gp91phox, and this in turn led to apoptosis. AOPPs treatment resulted in β-cell apoptosis, AOPPs accumulation, and decreased insulin content in pancreas and plasma in unilateral nephrectomized rats. Chronic inhibition of NADPH oxidase by apocynin prevented β-cell apoptosis and ameliorated insulin deficiency in AOPP-challenged rats. This study demonstrates for the first time that accumulation of AOPPs promotes NADPH oxidase-dependent β-cell destruction and dysfunction by the Bcl-2/Bax-caspase apoptotic pathway. This finding may provide a mechanistic explanation for β-cell destruction and dysfunction in patients with diverse disorders.
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Clinical Specialty Discipline Construction Program, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Clinical Specialty Discipline Construction Program, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China.
authors.forename: Aiqing
authors.initials: A
authors.lastname: Li
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Clinical Specialty Discipline Construction Program, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China.
authors.forename: Aiju
authors.initials: A
authors.lastname: Lou
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Clinical Specialty Discipline Construction Program, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China.
authors.forename: Xifang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Clinical Specialty Discipline Construction Program, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China.
authors.forename: Youyuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Clinical Specialty Discipline Construction Program, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Clinical Specialty Discipline Construction Program, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Clinical Specialty Discipline Construction Program, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China.
authors.forename: Shenglin
authors.initials: S
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Clinical Specialty Discipline Construction Program, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China.
authors.forename: Fan Fan
authors.initials: FF
authors.lastname: Hou
mesh_terms: D062107:Advanced Oxidation Protein Products / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism*; D010179:Pancreas / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D062107:Advanced Oxidation Protein Products; C494828:Bax protein, rat; D051028:bcl-2-Associated X Protein; D019255:NADPH Oxidases