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Involvement of the RAGE/AGE axis in macrophage lipid accumulation induced by human advanced glycated albumin

Grant number: 14/05951-6
Support Opportunities:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): July 24, 2014
Effective date (End): September 14, 2014
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Marisa Passarelli
Grantee:Adriana Machado Saldiba de Lima
Supervisor: Ann Marie Schmidt
Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: NYU Langone Medical Center, United States  
Associated to the scholarship:12/19112-0 - Involvement of the RAGE/AGE axis in macrophage lipid accumulation induced by human advanced glycated albumin - contribution of glycemic control in diabetes mellitus., BP.PD


Advanced glycation end products (AGE) are elevated in diabetes mellitus (DM) and predict the development of atherosclerosis. AGE-albumin induces oxidative stress that is linked to the reduction in ABCA-1 levels and macrophage cholesterol accumulation. We analyzed if the effect of AGE-albumin in disturbing macrophage reverse cholesterol transport (RCT) can be prevented by silencing or knocking out the receptor for AGE (RAGE). AGE-albumin was isolated from poorly controlled type 1 (DM1) and type 2 (DM2) DM patients' serum (HbA1c > 8%) and control albumin (C) from healthy subjects by FPLC and alcohol extraction. Bone marrow macrophages isolated from RAGE knockout (RAGE-KO) and wild-type (WT) mice and THP-1 cells transfected with siRNA-RAGE were treated for 48 h with C, DM1 or DM2-albumin in order to measure NOX-4 (NADPHoxidase4) and RAGE (Ager) expression and the apo A-I and HDL subfractions-mediated cholesterol efflux. Data were compared by one-way ANOVA and Dunnet´s post test. A 71% silencing in RAGE expression was attained in THP-1 cells treated with siRNA-RAGE. In those cells, expressions of RAGE and NOX-4 were reduced by DM1 and DM2-albumin treatment and no changed by C-albumin as compared to scramble siRNA transfected cells. In WT cells, cholesterol efflux to apo A-I and HDL subfractions was reduced by DM1 and DM2-albumin in comparison to C-albumin. These reductions were not observed when RAGE-KO cells were treated with DM1 and DM2-albumin in comparison to C-albumin.Induction of oxidative stress and impairment in cholesterol efflux elicited in macrophages by AGE-albumin drawn from DM patients can be prevented by inhibiting RAGE. AGE blockers might be useful in preventing derangements in RCT and atherosclerosis in poorly controlled DM. In order to continue this investigation we plan to transfect THP-1 cell with si-RAGE or treat J774 with anti-RAGE to conclude gene expression experiments. In additon we are going to treat bone marrow macrophages (BMM) isolated from RAGE knockout (RAGE-KO) and wild-type (WT) mice to access intracellular lipid accumulation with Oil Red O. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MACHADO-LIMA, ADRIANA; LOPEZ-DIEZ, RAQUEL; IBORRA, RODRIGO TALLADA; PINTO, RAPHAEL DE SOUZA; DAFFU, GURDIP; SHEN, XIAOPING; NAKANDAKARE, EDNA REGINA; MACHADO, UBIRATAN FABRES; CORREA-GIANNELLA, MARIA LUCIA CARDILLO; SCHMIDT, ANN MARIE; et al. RAGE Mediates Cholesterol Efflux Impairment in Macrophages Caused by Human Advanced Glycated Albumin. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 21, n. 19, . (12/19112-0, 15/21072-5, 13/06800-9, 18/00172-0, 13/26256-1, 12/12088-7, 14/05951-6, 16/15603-0)

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