title: The receptor of advanced glycation end products plays a central role in advanced oxidation protein products-induced podocyte apoptosis.
abstract: The accumulation of plasma advanced oxidation protein products (AOPPs) is prevalent in chronic kidney disease. We previously showed that accumulation of AOPPs resulted in podocyte apoptosis and their deletion by a cascade of signaling events coupled with intracellular oxidative stress. The transmembrane receptor that specifically transmits the AOPPs' signals to elicit cellular activity, however, remains unknown. Using co-immunoprecipitation and immunofluorescence, we found that AOPPs colocalized and interacted with the receptor of advanced glycation end products (RAGE) on podocytes. Blocking RAGE by anti-RAGE immunoglobulin G or its silencing by siRNA significantly protected podocytes from AOPPs-induced apoptosis both in vitro and in vivo and ameliorated albuminuria in AOPPs-challenged mice. AOPPs-induced activation of nicotinamide adenine dinucleotide phosphate oxidase and the excessive generation of intracellular superoxide were largely inhibited by anti-RAGE immunoglobulin G or RAGE siRNA. Moreover, blockade of RAGE decreased the activation of the p53/Bax/caspase-dependent proapoptotic pathway induced by AOPPs. Thus, AOPPs interact with RAGE to induce podocyte apoptosis and this, in part, may contribute to the progression of chronic kidney disease.
authors.affiliation: Key Lab for Organ Failure Research, Ministry of Education, Division of Nephrology, Research Institute of Nephrology Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Li Li
authors.initials: LL
authors.lastname: Zhou
authors.forename: Wei
authors.initials: W
authors.lastname: Cao
authors.forename: Chao
authors.initials: C
authors.lastname: Xie
authors.forename: Jianwei
authors.initials: J
authors.lastname: Tian
authors.forename: Zhanmei
authors.initials: Z
authors.lastname: Zhou
authors.forename: Qiugen
authors.initials: Q
authors.lastname: Zhou
authors.forename: Ping
authors.initials: P
authors.lastname: Zhu
authors.forename: Aiqing
authors.initials: A
authors.lastname: Li
authors.forename: Youhua
authors.initials: Y
authors.lastname: Liu
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
authors.forename: Fan Fan
authors.initials: FF
authors.lastname: Hou
authors.forename: Jing
authors.initials: J
authors.lastname: Nie
mesh_terms: D062107:Advanced Oxidation Protein Products / Q000008:administration & dosage / Q000378:metabolism*; D000419:Albuminuria / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D018450:Disease Progression; D004789:Enzyme Activation; D005455:Fluorescent Antibody Technique; D007074:Immunoglobulin G / Q000008:administration & dosage; D047468:Immunoprecipitation; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000378:metabolism; D050199:Podocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D062107:Advanced Oxidation Protein Products; C494827:Bax protein, mouse; D007074:Immunoglobulin G; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D013481:Superoxides; D019255:NADPH Oxidases; C505409:Casp3 protein, mouse; D053148:Caspase 3