Gut microbial metabolite butyrate protects against proteinuric kidney disease through epigenetic- and GPR109a-mediated mechanisms

Autor(es):Mostrar menos -

Felizardo, Raphael J. F. ^{[1, 2, 3]} ; de Almeida, Danilo C. ^{[1, 3]} ; Pereira, Rafael L. ^[4] ; Watanabe, Ingrid K. M. ^{[1, 3]} ; Doimo, Nayara T. S. ^[5] ; Ribeiro, Willian R. ^[6] ; Cenedeze, Marcos A. ^[1] ; Hiyane, Meire I. ^[3] ; Amano, Mariane T. ^{[3, 5]} ; Braga, Tarcio T. ^[3] ; Ferreira, Caroline M. ^[6] ; Parmigiani, Raphael B. ^[7] ; Andrade-Oliveira, Vinicius ^[3] ; Volpini, Rildo A. ^[8] ; Vinolo, Marco Aurelio R. ^[9] ; Marino, Eliana ^[2] ; Robert, Remy ^[2] ; Mackay, Charles R. ^[2] ; Camara, Niels O. S. ^{[1, 3]}

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Dept Med, Nephrol Div, Sao Paulo - Brazil

^[2] Monash Univ, Dept Biochem & Mol Biol, Biodiscovery Inst, Clayton, Vic - Australia

^[3] Univ Sao Paulo, Fac Med, Inst Biomed Sci 4, Dept Immunol, Sao Paulo - Brazil

^[4] Univ Fed Parana, Dept Physiol, Curitiba, Parana - Brazil

^[5] Hosp Sirio Liban es, Ctr Mol Oncol, Sao Paulo - Brazil

^[6] Univ Fed Sao Paulo, Inst Environm Chem & Pharmaceut Sci, Dept Pharmaceut Sci, Diadema - Brazil

^[7] Idengene Med Diagnost, Sao Paulo - Brazil

^[8] Univ Sao Paulo, Fac Med, Hosp Clin HCFMUSP, LIM12, Sao Paulo - Brazil

^[9] Univ Estadual Campinas, Inst Biol, Dept Genet Evolut Microbiol & Immunol, Campinas - Brazil

• Tipo de documento: Artigo Científico
• Fonte: FASEB JOURNAL; v. 33, n. 11, p. 11894-11908, NOV 2019.
• Citações Web of Science: 0

Resumo

Butyrate is a short-chain fatty acid derived from the metabolism of indigestible carbohydrates by the gut microbiota. Butyrate contributes to gut homeostasis, but it may also control inflammatory responses and host physiology in other tissues. Butyrate inhibits histone deacetylases, thereby affecting gene transcription, and also signals through the metabolite-sensing G protein receptor (GPR)109a. We produced an mAb to mouse GPR109a and found high expression on podocytes in the kidney. Wild-type and Gpr109a(-/-) mice were induced to develop nephropathy by a single injection of Adriamycin and treated with sodium butyrate or high butyrate-releasing high-amylose maize starch diet. Butyrate improved proteinuria by preserving podocyte at glomerular basement membrane and attenuated glomerulosclerosis and tissue inflammation. This protective phenotype was associated with increased podocyte-related proteins and a normalized pattern of acetylation and methylation at promoter sites of genes essential for podocyte function. We found that GPR109a is expressed by podocytes, and the use of Gpr109a(-/-) mice showed that the protective effects of butyrate depended on GPR109a expression. A prebiotic diet that releases high amounts of butyrate also proved highly effective for protection against kidney disease. Butyrate and GPR109a play a role in the pathogenesis of kidney disease and provide one of the important molecular connections between diet, the gut microbiota, and kidney disease. (AU)

• Processo FAPESP: 14/13135-4 - O papel dos receptores sensíveis a metabólitos (GPR41, GPR43 e GPR109A) e das vias epigenéticas para a progressão de nefropatias
• Beneficiário: Raphael Jose Ferreira Felizardo
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado Direto
• Processo FAPESP: 12/02270-2 - Novos mecanismos celulares, moleculares e imunológicos das lesões renais agudas e crônicas: busca por novas estratégias terapêuticas
• Beneficiário: Niels Olsen Saraiva Câmara
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 12/15205-4 - Papel dos ácidos graxos de cadeia curta na glomeruloesclerose segmentar e focal experimental
• Beneficiário: Raphael Jose Ferreira Felizardo
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 12/50410-8 - Efeito dos ácidos graxos de cadeia curta produzidos por bactérias probióticas na profilaxia e tratamento da inflamação alérgica das vias aéreas
• Beneficiário: Caroline Marcantonio Ferreira
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 17/05264-7 - Metabolismo celular, microbiota e sistema imune: novos paradigmas na fisiopatologia das doenças renais
• Beneficiário: Niels Olsen Saraiva Câmara
• Modalidade de apoio: Auxílio à Pesquisa - Temático