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

• Grant number: 17/05264-7
• Support Opportunities: Research Projects - Thematic Grants
• Duration: April 01, 2018 - March 31, 2024
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Niels Olsen Saraiva Câmara
• Grantee: Niels Olsen Saraiva Câmara
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Pesquisadores principais: Alvaro Pacheco e Silva Filho
• Associated 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): 23/06109-6 - Role of Histone deacetylases in NF-kB pathway signaling in cisplatin-induced liver and kidney injuries in zebrafish, BP.IC; 23/09465-8 - Maintenance of the zebrafish facility at the Transplantation Immunobiology Laboratory., BP.TT; 22/12833-6 - Effect of caloric restriction on cGAS-STING signaling on acute kidney injury in zebrafish, BP.DR; + associated scholarships 23/02889-7 - TRPM5 ION CHANNEL INFLUENCE ON T LYMPHOCYTE ACTIVATION IN A MURINE MODEL OF TYPE 1 DIABETES MELLITUS, BP.IC; 22/16820-6 - Role of peroxisomal biogenesis in the protective effects of caloric restriction in cisplatin-induced Acute Kidney Injury, BP.PD; 22/16176-0 - The role of SARMI in CD4 T cell activation and differentiation, BP.DR; 22/13074-1 - Regulation of the Th17/Treg axis by HIF-1a in experimental type 1 diabetes susceptibility, BP.IC; 22/13122-6 - Role of Pink1-Mediated Mythophagy in Keratinocytes in the Development of Inflammation in Experimental Psoriasis Model, BP.IC; 22/13419-9 - THE ROLE OF THE GUT-SKIN AXIS IN THE REJECTION OF ALLOGENIC TRANSPLANTS IN A MURINE EXPERIMENTAL MODEL, BP.IC; 22/13355-0 - Maintenance of the zebrafish facility of the Transplantation Immunobiology Laboratory., BP.TT; 22/02682-0 - Co-culture of human tumor cells with zebrafish blastoderm cells: study of the tumor microenvironment, BP.IC; 22/01035-1 - Managementy of zebrafish core facility from the Transplantation Immunobiology Laboratory, BP.TT; 22/01961-3 - Creation and maintenance of transgenic lines, BP.TT; 21/14553-8 - Mechanisms of Trimethylamine-N-oxide (TMAO) in the progression of acute kidney injury in obesity., BP.PD; 21/09718-8 - Influence of the immune system on the induction of ferroptosis in tumor cells, BP.IC; 20/10263-2 - Role of histones deacetylases in regeneration and macrophage polarization in post-inducing acute kidney injury in Zebrafish (Danio rerio), BP.DR; 19/21359-3 - Evaluation of cross-talking between renal pericets and mesangial cells during Diabetic Nephropathy, BP.DR; 20/06800-2 - Cellular metabolism and tumorigenesis: the role of growth hormone and mitochondrial dynamics in the Zebrafish experimental model, BP.PD; 20/14388-4 - Incretin signal in tumor progression in the experimental model of Colorectal Cancer associated with Colitis, BP.DD; 21/00946-8 - Effects of fructose rich diet on reactive oxygen species production in Acute Kidney Injury Zebrafish model, BP.DD; 20/04592-3 - The role of the intracellular DNA sensor, AIM2, and signaling molecules, STING and MAVS, in proximal tubular epithelial cell metabolism in kidney fibrosis development, BP.PD; 20/04430-3 - Role of the PKM2 enzyme in the regulation of the immune and metabolic responses of keratinocytes in an experimental model of skin transplantation, BP.DD; 20/04408-8 - The role of NLRP1 inflamassome in the antitumor response of Th17 limphocytes, BP.MS; 20/04774-4 - Study of inflammatory and metabolic pathways in zebrafish, BP.TT; 19/22409-4 - Role of acetate in ischemia and reperfusion-induced mitochondrial injury and renal injury, BP.IC; 19/15166-8 - DNA repair, metabolism and the inflammatory immune response triggered by ischemia and reperfusion injury, BP.PD; 19/09679-2 - Characterization of PPARgamma knockout macrophages subpopulation in breast cancer model and the influence of moderate aerobic training, BP.PD; 19/16079-1 - Importance of mTOR complex 2 (mTORC2) and AMPK in neutrophils to Melanoma progression, BP.PD; 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; 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; 18/18702-5 - Metabolic pathways in renal cells and the progression of renal diseases, BP.TT; 18/17513-4 - The relationship between NRLP3 inflammasome and glycolytic metabolism of tubular epithelial cells in the development of renal fibrosis, BP.PD; 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

(24)

(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)

FENERO, CAMILA MORALES; PADOVANI, BARBARA NUNES; DO AMARAL, MARIANA ABRANTES; BOTTURA DE BARROS, GUILHERME JOSE; XAVIER DE OLIVEIRA, IZABELLA KARINA; HIYANE, MEIRE IOSHIE; SARAIVA CAMARA, NIELS OLSEN. Acute Kidney Injury Model Induced by Cisplatin in Adult Zebrafish. JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, n. 171, MAY 2021. (17/05687-5, 15/21644-9, 18/20722-4, 17/05264-7)

YARIWAKE, VICTOR YUJI; TORRES, JANAINA IANNICELLI; DOS SANTOS, AMANDDA RAKELL PEIXOTO; FREITAS, SARAH CRISTINA FERREIRA; DE ANGELIS, KATIA; FARHAT, SYLVIA COSTA LIMA; CAMARA, NIELS OLSEN SARAIVA; VERAS, MARIANA MATERA. Chronic exposure to PM2.5 aggravates SLE manifestations in lupus-prone mice. PARTICLE AND FIBRE TOXICOLOGY, v. 18, n. 1, MAR 25 2021. (17/05264-7, 18/05187-5)

BRAGA, TARCIO TEODORO; DAVANSO, MARIANA RODRIGUES; MENDES, DAVI; DE SOUZA, TIAGO ANTONIO; DE BRITO, ANDERSON FERNANDES; CRUZ, MARIO COSTA; HIYANE, MEIRE IOSHIE; DE LIMA, DHEMERSON SOUZA; NUNES, VINICIUS; GIAROLA, JULIANA DE FATIMA; et al. Sensing soluble uric acid by Naip1-Nlrp3 platform. CELL DEATH & DISEASE, v. 12, n. 2, FEB 5 2021. (17/05264-7, 14/06992-8)

SANTORO, DALTON DE FREITAS; DE SOUSA, LUCIENE BARBOSA; CAMARA, NIELS O. S.; DE FREITAS, DENISE; DE OLIVEIRA, LAURO AUGUSTO. SARS-COV-2 and Ocular Surface: From Physiology to Pathology, a Route to Understand Transmission and Disease. FRONTIERS IN PHYSIOLOGY, v. 12, FEB 12 2021. (17/05264-7)

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. (17/05264-7, 17/22504-1, 14/06992-8)

ALBERCA-CUSTODIO, RICARDO WESLEY; FAUSTINO, LUCAS D.; GOMES, ELIANE; NUNES, FERNANDA PEIXOTO BARBOSA; DE SIQUEIRA, MIRIAN KRYSTEL; LABRADA, ALEXIS; ALMEIDA, RAFAEL RIBEIRO; CAMARA, NIELS OLSEN SARAIVA; DA FONSECA, DENISE MORAIS; RUSSO, MOMTCHILO. Allergen-Specific Immunotherapy With Liposome Containing CpG-ODN in Murine Model of Asthma Relies on MyD88 Signaling in Dendritic Cells. FRONTIERS IN IMMUNOLOGY, v. 11, APR 23 2020. (15/25364-0, 15/16728-9, 14/19906-2, 13/24694-1, 17/05264-7, 16/16602-8)

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. (15/15626-8, 15/26682-6, 14/10910-7, 17/05264-7, 16/18031-8)

FELIZARDO, RAPHAEL J. F.; DE ALMEIDA, DANILO C.; PEREIRA, RAFAEL L.; WATANABE, INGRID K. M.; DOIMO, NAYARA T. S.; RIBEIRO, WILLIAN R.; CENEDEZE, MARCOS A.; HIYANE, MEIRE I.; AMANO, MARIANE T.; BRAGA, TARCIO T.; et al. Gut microbial metabolite butyrate protects against proteinuric kidney disease through epigenetic- and GPR109a-mediated mechanisms. FASEB JOURNAL, v. 33, n. 11, p. 11894-11908, NOV 2019. (14/13135-4, 12/02270-2, 12/15205-4, 12/50410-8, 17/05264-7)

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; et al. L-Arginine supplementation blunts resistance exercise improvement in rats with chronic kidney disease. Life Sciences, v. 232, SEP 1 2019. (17/05264-7, 12/02270-2)

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. (17/05264-7, 15/26682-6)

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. (12/15205-4, 17/06222-6, 17/05264-7, 12/02270-2, 16/08907-3)

ALBINO, AMANDA HELEN; FREGNAN ZAMBOM, FERNANDA FLORENCIA; FORESTO-NETO, ORESTES; OLIVEIRA, KARIN CARNEIRO; AVILA, VICTOR FERREIRA; ALARCON ARIAS, SIMONE COSTA; SEGURO, ANTONIO CARLOS; AVANCINI COSTA MALHEIROS, DENISE MARIA; SARAIVA CAMARA, NIELS OLSEN; FUJIHARA, CLARICE KAZUE; et al. Renal Inflammation and Innate Immune Activation Underlie the Transition From Gentamicin-Induced Acute Kidney Injury to Renal Fibrosis. FRONTIERS IN PHYSIOLOGY, v. 12, JUL 7 2021. (17/05264-7, 12/10926-5)

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; et al. Extracellular Vesicles isolated from Mesenchymal Stromal Cells Modulate CD4(+) T Lymphocytes Toward a Regulatory Profile. CELLS, v. 9, n. 4, APR 2020. (17/05264-7, 18/08479-7, 14/07390-1, 16/13029-5)

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. (19/02893-9, 12/10926-5, 18/17513-4, 17/05264-7)

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. (17/05264-7)

BRAGA, TARCIO TEODORO; FORESTO-NETO, ORESTES; SARAIVA CAMARA, NIELS OLSEN. The role of uric acid in inflammasome-mediated kidney injury. CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION, v. 29, n. 4, p. 423-431, JUL 2020. (19/02893-9, 18/08479-7, 17/05264-7)

PAREDES, LAIS CAVALIERI; LUZ, REBECA BOSSO DOS SANTOS; TOZZI, OLLAVO NOGUEIRA; DE CARVALHO, LUCICLEIDE ANGELO SILVA JUNGLES; CALADO, SABRINA LOISE DE MORAIS; PADOVANI, BARBARA NUNES; FENERO, CAMILA IDELI MORALES; DO AMARAL, MARIANA ABRANTES; DE ASSIS, HELENA CRISTINA DA SILVA; CAMARA, NIELS OLSEN SARAIVA; et al. Distinct macrophage phenotypes and redox environment during the fin fold regenerative process in zebrafish. Scandinavian Journal of Immunology, v. 94, n. 2, FEB 2021. (17/05264-7)

FILGUEIRAS, IGOR SALERNO; TORRENTES DE CARVALHO, AMANDA; CUNHA, DANIELA PRADO; MATHIAS DA FONSECA, DENNYSON LEANDRO; EL KHAWANKY, NADIA; FREIRE, PAULA PACCIELLI; CABRAL-MIRANDA, GUSTAVO; SCHIMKE, LENA F.; CAMARA, NIELS OLSEN SARAIVA; OCHS, HANS D.; et al. The clinical spectrum and immunopathological mechanisms underlying ZIKV-induced neurological manifestations. PLoS Neglected Tropical Diseases, v. 15, n. 8, AUG 2021. (18/18886-9, 20/09146-1, 17/05264-7, 20/01688-0)

TARGHETTA, VITOR PEDRO; AMARAL, MARIANA ABRANTES; SARAIVA CAMARA, NIELS OLSEN. Through DNA sensors and hidden mitochondrial effects of SARS-CoV-2. Journal of Venomous Animals and Toxins including Tropical Diseases, v. 27, AUG 23 2021. (17/05264-7, 15/21644-9, 20/04408-8, 21/00946-8)

WATANABE, INGRID KAZUE MIZUNO; ANDRADE-SILVA, MAGAIVER; FORESTO-NETO, ORESTES; FELIZARDO, RAPHAEL JOSE FERREIRA; MATHEUS, MARCO AURELIO COSTA; SILVA, REINALDO CORREA; CENEDEZE, MARCOS ANTONIO; HONDA, TAMISA SEEKO BANDEIRA; PERANDINI, LUIZ AUGUSTO BUORO; VOLPINI, RILDO APARECIDO; et al. Gut Microbiota and Intestinal Epithelial Myd88 Signaling Are Crucial for Renal Injury in UUO Mice. FRONTIERS IN IMMUNOLOGY, v. 11, DEC 22 2020. (14/50833-1, 17/05264-7, 19/19435-3)

LEITE, JEFFERSON A.; GHIROTTO, BRUNO; TARGHETTA, VITOR P.; DE LIMA, JEAN; CAMARA, NIELS O. S.. Sirtuins as pharmacological targets in neurodegenerative and neuropsychiatric disorders. British Journal of Pharmacology, JUN 2021. (17/05264-7)

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. (17/05264-7)

PEREIRA, V, FELIPE; MELO, AMANDA C. L.; SILVA, MARINA B.; DE MELO, FILIPE M.; TERRA, FERNANDA F.; CASTRO, IRIS A.; PERANDINI, LUIZ A.; MIYAGI, MARCELLI T.; SATO, FABIO T.; ORIGASSA, CLARICE S. T.; et al. Interleukin-6 and the Gut Microbiota Influence Melanoma Progression in Obese Mice. NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL, v. 73, n. 4, MAY 2020. (13/10318-8, 17/05264-7)

FREIRE, PAULA P.; MARQUES, ALEXANDRE H. C.; BAIOCCHI, GABRIELA C.; SCHIMKE, LENA F.; FONSECA, DENNYSON L. M.; SALGADO, RANIERI C.; FILGUEIRAS, IGOR S.; NAPOLEAO, SARAH M. S.; PLACA, DESIREE R.; AKASHI, KAREN T.; et al. The relationship between cytokine and neutrophil gene network distinguishes SARS-CoV-2-infected patients by sex and age. JCI INSIGHT, v. 6, n. 10, MAY 24 2021. (20/09146-1, 20/01688-0, 17/05264-7, 13/50343-1, 20/07069-0, 20/07972-1)