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Modulation of mTOR signaling pathway in macrophages in the progression of focal and segmental glomerulosclerosis

Grant number: 12/05605-5
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): August 01, 2012
Effective date (End): March 31, 2015
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Niels Olsen Saraiva Câmara
Grantee:Rafael Luiz Pereira
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The focal and segmental glomerulosclerosis (FSGS) is a major cause chronic kidney disease (CKD) in the world. FSGS is characterized by massive proteinuria associated with involvement of epithelial cells (podocytes). Experimental models classical FSGS can be induced by administration of chemotherapeutic drugs such as adriamycin (ADM). The model of nephropathy induced by ADM mimics the classic signs of human FSGS, as proteinuria associated with glomerular and tubular lesions. Among the mechanisms associated with podocyte injury, pro-inflammatory molecules as IFN-³, TNF-± and TGF-², which are produced principally by macrophages, are well described. Macrophages are extremely important in triggering inflammation and are associated with fibrosis, so it is a common finding in several renal pathologies such as FSGS. These cells have a high plasticity, being associated with several subtypes with different functions, which are modulated by several cytokines, transcription factors and metabolic pathways. Among the metabolic pathways associated with modulation of macrophages, mTOR pathway has gained a lot of attention. It was found that this pathway acts directly on proliferation, differentiation and activation of cells. Several factors that regulate mTOR pathway, such as GTPase RHEB, positively, and, negatively, the Tuberous Sclerosis as Complex (TSC) and Rapamycin, which has already been used as an immunosuppressant. Given that, several studies suggest a potential role of macrophages in kidney disease, especially in FSGS, as previously seen by our group, we intend to determine the role of mTOR pathway in the modulation of macrophages in this disease, making use of knockout animals to study mTOR signaling and chemokines associated with macrophage migration/activation, but also the involvement of these cells in the podocyte lesione in vitro studies.

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)
PEREIRA, RAFAEL LUIZ; FERREIRA FELIZARDO, RAPHAEL JOSE; CENEDEZE, MARCOS ANTOINO; HIYANE, MEIRE IOSHIE; BASSI, ENIO JOSE; AMANO, MARIANE TAMI; TAEMI ORIGASSA, CLARICE SYLVIA; SILVA, REINALDO CORREIA; AGUIAR, CRISTHIANE FAVERO; CARNEIRO, SYLVIA MENDES; PESQUERO, JOAO BOSCO; ARAUJO, RONALDO CARVALHO; KELLER, ALEXANDRE DE CASTRO; MONTEIRO, RENATO C.; MOURA, IVAN CRUZ; PACHECO-SILVA, ALVARO; SARAIVA CAMARA, NIELS OLSEN. Balance between the two kinin receptors in the progression of experimental focal and segmental glomerulosclerosis in mice. Disease Models & Mechanisms, v. 7, n. 6, p. 701-710, JUN 2014. Web of Science Citations: 6.

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