The phenotypic polarization of macrophages between the classic and alternative patterns, as well as the differentiation of CD4+ T lymphocytes from naive to effector cells, involves a deep change on a cell metabolic profile, change in which the adenosine monophosphate activated kinase (AMPK) plays a central role. This protein acts as a sensor of nutrients availability and energetic resources, aiding the cell to adequate itself in situations of metabolic stress. Several recent studies have been demonstrating the importance of this molecule in the phenomena of metabolism plasticity and energetic homeostasis, and its insertion on signaling pathways with a counter-regulatory effect on inflammation. In face of those multiple roles, a possible practical application of the modulation of AMPK is foreseen in the therapy of diseases whose ethiopathogenic mechanisms include chronic inflammation and tissue fibrosis. Chronic kidney disease (CKD) is a relevant condition for its impact on the morbidity and mortality it brings to the patients. Nowadays, it is well established the role of inflammation on the progression of CKD. As such, we aim to investigate the role of AMPK on macrophages and T cells in a murine model of CKD. CKD will be induced by the feeding of adenine-enriched (0.25%) food to wild mice C57BL/6 (WT) and to mice with deletion of the AMPK gene specifically on macrophages and CD4+ T cells. After 10 days, the mice will be euthanized and kidney tissue will be evaluated on its histology and immunohistochemistry, gene expression of inflammatory cytokines, pro-fibrotic citokines and molecules of the cell metabolism, protein expression of AMPK, and characterization of the cell infiltrate. Additionally, the mice will be treated with metformin, an agonist of the AMPK pathway. We aim to demonstrate that the absence of a metabolism sensor in the target cells of the inflammatory process on experimental CKD lessens its progression and, consequently, provide better outcomes of renal function. Thus, our project intends to add an innovative element on the current knowledge about inflammation on the progression of CKD. We hope to stress out a role for metabolic sensors in the activation of immune cells relevant for the development of fibrosis and this achievement could accelerate the translation into clinic.
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