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Cell metabolism, microbiota and immune system: new paradigms in renal diseases physiopathology

Grant number: 17/05264-7
Support type:Research Projects - Thematic Grants
Duration: April 01, 2018 - March 31, 2023
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Niels Olsen Saraiva Câmara
Grantee:Niels Olsen Saraiva Câmara
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Co-Principal Investigators:Alvaro Pacheco e Silva Filho
Assoc. researchers:Caroline Marcantonio Ferreira ; Christian Hoffmann ; Clarice Kazue Fujihara ; Daniela Carlos Sartori ; Denise Maria Avancini Costa Malheiros ; Denise Morais da Fonseca ; Flaviano dos Santos Martins ; João Santana da Silva ; José Carlos Farias Alves Filho ; Pedro Manoel Mendes de Moraes Vieira ; Roberto Zatz ; Thiago Mattar Cunha
Associated grant(s):18/08479-7 - Multi-user equipment approved in grant 17/05264-7: analisador de fluxo extracelular Seahorse XFe96, AP.EMU
Associated scholarship(s):18/24350-4 - Metabolic characterization of Foxp3+ RORgt+ T cell population in the experimental model of Colitis-associated colorectal Cancer, BP.DD
19/02893-9 - The hypoxia-inducible factor 1 alpha (HIF-1 alpha) and the metabolism of tubular epithelial cells and podocytes in the development and progression of experimental kidney disease, BP.PD
18/23460-0 - Evaluation of the mitochondrial dynamics in astrocytes and its impact on the inflammatory response in experimental autoimmune encephalomyelitis, BP.MS
+ associated scholarships 18/21844-6 - Cell metabolism and mitochondrial dynamics in kidney ischemia-reperfusion injury: a role for heme oxygenase 1, BP.IC
18/18701-9 - Study of inflammatory and metabolic pathways in zebrafish, BP.TT
18/20722-4 - Study of the effects of diet rich in fructose and vitamin's role in regulating inflammation in acute renal injury model in zebrafish, BP.IC
18/17513-4 - The relationship between NRLP3 inflammasome and glycolytic metabolism of tubular epithelial cells in the development of renal fibrosis, BP.PD
18/18702-5 - Metabolic pathways in renal cells and the progression of renal diseases, BP.TT
18/06338-7 - Evaluation of genotoxicity associated to experimental obesity, BP.IC - associated scholarships

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 (8)
(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)
ANDRADE-OLIVEIRA, VINICIUS; FORESTO-NETO, ORESTES; MIZUNO WATANABE, INGRID KAZUE; ZATZ, ROBERTO; SARAIVA CAMARA, NIELS OLSEN. Inflammation in Renal Diseases: New and Old Players. FRONTIERS IN PHARMACOLOGY, v. 10, OCT 8 2019. Web of Science Citations: 0.
BRAGA, TARCIO TEODORO; BRANDAO, WESLEY NOGUEIRA; AZEVEDO, HATYLAS; TERRA, FERNANDA FERNANDES; MELO, AMANDA CAMPELO L.; PEREIRA, FELIPE VALENCA; ANDRADE-OLIVEIRA, VINICIUS; HIYANE, MEIRE IOSHIE; PERON, JEAN PIERRE S.; SARAIVA CAMARA, NIELS OLSEN. NLRP3 gain-of-function in CD4(+) T lymphocytes ameliorates experimental autoimmune encephalomyelitis. Clinical Science, v. 133, n. 17, p. 1901-1916, SEP 13 2019. Web of Science Citations: 0.
SOUZA, MICHEL KENDY; MORAES, MILTON ROCHA; ROSA, THIAGO SANTOS; PASSOS, CLEVIA SANTOS; PASSOS NEVES, RODRIGO VANERSON; HARO, ANDERSON SOLA; CENEDEZE, MARCOS ANTONIO; ALARCON ARIAS, SIMONE COSTA; FUJIHARA, CLARICE KAZUE; TEIXEIRA, SIMONE APARECIDA; MUSCARA, MARCELO NICOLAS; SARAIVA CAMARA, NIELS OLSEN; PACHECO E SILVA FILHO, ALVARO. L-Arginine supplementation blunts resistance exercise improvement in rats with chronic kidney disease. Life Sciences, v. 232, SEP 1 2019. Web of Science Citations: 0.
DE SOUZA BREDA, CRISTIANE NAFFAH; DAVANZO, GUSTAVO GASTAO; BASSO, PAULO JOSE; SARAIVA CAMARA, NIELS OLSEN; MENDES MORAES-VIEIRA, PEDRO MANOEL. Mitochondria as central hub of the immune system. REDOX BIOLOGY, v. 26, SEP 2019. Web of Science Citations: 2.
PAREDES, LAIS CAVALIERI; SARAIVA CAMARA, NIELS OLSEN; BRAGA, TARCIO TEODORO. Understanding the Metabolic Profile of Macrophages During the Regenerative Process in Zebrafish. FRONTIERS IN PHYSIOLOGY, v. 10, MAY 24 2019. Web of Science Citations: 0.
FELIZARDO, R. J. F.; WATANABE, I. K. M.; DARDI, PATRIZIA; ROSSONI, L. V.; CAMARA, N. O. S. The interplay among gut microbiota, hypertension and kidney diseases: The role of short-chain fatty acids. PHARMACOLOGICAL RESEARCH, v. 141, p. 366-377, MAR 2019. Web of Science Citations: 3.
BASSO, PAULO JOSE; SARAIVA CAMARA, NIELS OLSEN; SALES-CAMPOS, HELIOSWILTON. Microbial-Based Therapies in the Treatment of Inflammatory Bowel Disease - An Overview of Human Studies. FRONTIERS IN PHARMACOLOGY, v. 9, JAN 10 2019. Web of Science Citations: 6.
REQUIAO-MOURA, LUCIO R.; MATOS, ANA C. C.; OZAKI, KIKUMI S.; CAMARA, NIELS O. S.; PACHECO-SILVA, ALVARO. A high level of urinary retinol-binding protein is associated with cytomegalovirus infection in kidney transplantation. Clinical Science, v. 132, n. 18, p. 2059-2069, SEP 28 2018. Web of Science Citations: 0.

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