Abstract
It is estimated that between 11 and 13% of the world population has chronic kidney disease (CKD). This scenario is particularly alarming when it is found that it may represent an underestimate ratio, and the diagnosis is usually late, since patients do not usually present complaints except in advanced stages, when renal replacement therapy becomes mandatory. CKD is an indolent and asymptomatic condition in its early stages, another reason for the under diagnosis. In fact, as with other chronic degenerative diseases with which it shares risk factors, such as systemic arterial hypertension, diabetes mellitus and, more recently, obesity, CKD falls into the category of preventable diseases. Thus, active investigation of its causal factors, coupled with early intervention, is currently the main strategy available to try to reduce its prevalence. Despite a knowledge of a cost-effective approach to contain its spread, therapeutic options for the more than 200 million patients already living with the disease are scarce, so that, annually, about 850 thousand individuals die DRC, which is the 12th cause of mortality in the world. It is known that regardless of the underlying cause of deterioration of renal function, the pathophysiology of CKD involves a persistent state of local and systemic inflammation that results in loss of renal parenchyma, which is gradually replaced by fibrosis. Therefore, the identification of cellular and molecular targets that allow the interruption of an inflammatory cascade that tends to amplify and feedback, leading to the inexorable loss of function and to the anatomical destruction of the kidneys, represents the core of current research that seeks to overcome the problem. In this project, we believe that the interface - inflammatory response - cellular metabolism - microbiota - is central to the pathophysiology of renal lesions, and that its study implies the discovery of diagnostic and/or therapeutic tools. In this sense, acute kidney injury (AKI) and CKD are established inflammatory conditions, in which both innate and acquired immunity elements are essential in the elaboration of the inflammatory response. Today, inflammation is known to alter the metabolic status of an immune cell, and that the activation of a metabolic pathway leads to a cell-specific functional phenotype. Thus, we believe that renal cells also have their metabolic altered profile by inflammation and that this influences their functions and induces specific pathological states such as podocyte dysfunction and epithelial-mesenchymal transition. The inflammatory response and its consequences on the metabolic profile would be the result of the action of receptors, metabolic sensors, closely connected to receptors of innate immunity, such as inflammasomes. Further, we believe that this response may modulate and be also affected by the intestinal microbiota and thus maintain a positive feedback loop and perpetuate inflammation in renal injury. We use several in vivo and in vitro models of renal injuries, in wild type, cell reporters, knockout and conditional mice to reply all aims of our project. Moreover, we will use update readout technologies such as assessment of cell metabolism, global gene expression by RNASeq, cell image and metagonomic to identify mechanisms and not associative conclusions. We believe that by link metabolism, microbiota and inflammation will end with new insights into pathophysiology of AKI and CKD and be able to propose new therapeutic strategies. (AU)
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)
DA CUNHA, FLAVIA FRANCO;
ANDRADE-OLIVEIRA, VINICIUS;
DE ALMEIDA, DANILO CANDIDO;
DA SILVA, TAMIRIS BORGES;
DE SOUZA BREDA, CRISTIANE NAFFAH;
CRUZ, MARIO COSTA;
FAQUIM-MAURO, ELIANA L.;
CENEDEZE, MARCOS ANTONIO;
HIYANE, MEIRE IOSHIE;
PACHECO-SILVA, ALVARO;
CAVINATO, REGIANE APARECIDA;
TORRECILHAS, ANA CLAUDIA;
SARAIVA CAMARA, NIELS OLSEN.
Extracellular Vesicles isolated from Mesenchymal Stromal Cells Modulate CD4(+) T Lymphocytes Toward a Regulatory Profile.
CELLS,
v. 9,
n. 4
APR 2020.
Web of Science Citations: 0.