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The influence of mTOR pathway in macrophage modulation and its consequences in experimental chronic kidney disease

Grant number: 12/10435-1
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): October 01, 2012
Effective date (End): April 30, 2017
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Niels Olsen Saraiva Câmara
Grantee:Mariane Tami Amano
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:12/02270-2 - New cellular, molecular and immunological mechanisms involved in acute and chronic renal injury: the search for new therapeutical approaches, AP.TEM
Associated scholarship(s):14/20861-3 - The role of cohesin mutations in myeloid malignancies development, BE.EP.PD

Abstract

The mTOR signaling pathway can be activated by several molecules including insulin and IGF-1, besides it can also be activated after binding of immune system receptors as T cells (TCR), B cells (BCR) and toll-like receptors (TLR). There are two mTOR complexes, mTORC1 and mTORC2, that differ in crucial components of the signalization, as the presence of raptor and rictor respectively. Recently, it was demonstrated that Th1 and Th17 polarization required mTORC1 activation and the Th2 differentiation required mTORC2 activation. Taking into consideration that the macrophage differentiation to M1 depends on IFN-g and to M2 depends on IL-4 and IL-13, Th1 and Th2 cytokines respectively, we questioned whether M1/M2 polarization could depend on mTORC1 and/or mTORC2 activation. The macrophages subtypes differentiation seems to be fundamental in diseases physiopathogenis like chronic kidney disease. Then, we questioned whether M1/M2 polarization in this model could depend on mTORC1 and mTORC2 activation. Moreover, the macrophages subtypes differentiation seems to be fundamental to diseases physiopathogenia as chronic kidney disease (CKD). Thus, in this project, we aim to verify the role of mTOR complexes (mTORC1/2) in M1 and M2 macrophages polarization and verify the activation prevalence of these complexes in chroninc renal injury by inducing the unilateral ureteral obstruction (UUO). This study intend to investigate for the first time the role of mTORC1/2 in M1 and M2 modulation, and also in an unprecedented manner unveil the mechanisms of mTOR complexes in CKD development.

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)
AMANO, MARIANE T.; CASTOLDI, ANGELA; ANDRADE-OLIVEIRA, VINICIUS; LATANCIA, MARCELA T.; TERRA, FERNANDA F.; CORREA-COSTA, MATHEUS; BREDA, CRISTIANE N. S.; FELIZARDO, RAPHAEL J. F.; PEREIRA, WELBERT O.; DA SILVA, MARINA B.; MIYAGI, MARIANA Y. S.; AGUIAR, CRISTHIANE F.; HIYANE, I, MEIRE; SILVA, JOAO S.; MOURA, IVAN C.; CAMARA, NIELS O. S. The lack of PI3K gamma favors M1 macrophage polarization and does not prevent kidney diseases progression. International Immunopharmacology, v. 64, p. 151-161, NOV 2018. Web of Science Citations: 4.
SAITO MIYAGI, MARIANA YASUE; LATANCIA, MARCELA TEATIN; TESTAGROSSA, LEONARDO ABREU; DE ANDRADE-OLIVEIRA, VINICIUS; PEREIRA, WELBERT OLIVEIRA; HIYANE, MEIRE IOSHIE; ENJIU, LUCAS MACERATESI; PISCIOTTANO, MARCUS; LEITE SEELAENDER, MARILIA CERQUEIRA; SARAIVA CAMARA, NIELS OLSEN; AMANO, MARIANE TAMI. Physical exercise contributes to cisplatin-induced nephrotoxicity protection with decreased CD4+T cells activation. Molecular Immunology, v. 101, p. 507-513, SEP 2018. Web of Science Citations: 0.
SAITO MIYAGI, MARIANA YASUE; SEELAENDER, MARILIA; CASTOLDI, ANGELA; DE ALMEIDA, DANILO CANDIDO; NOVA BACURAU, ALINE VILLA; ANDRADE-OLIVEIRA, VINICIUS; ENJIU, LUCAS MACERATESI; PISCIOTTANO, MARCUS; HAYASHIDA, CAROLINE YURI; HIYANE, MEIRE IOSHIE; BRUM, PATRICIA CHAKUR; SARAIVA CAMARA, NIELS OLSEN; AMANO, MARIANE TAMI. Long-Term Aerobic Exercise Protects against Cisplatin-Induced Nephrotoxicity by Modulating the Expression of IL-6 and HO-1. PLoS One, v. 9, n. 10 OCT 1 2014. Web of Science Citations: 16.

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