O papel do acetato como modulador da lesão renal aguda induzida por cisplatina

• Ano de defesa: 2017
• Autor(a) principal: Cruz, Mário Costa [UNIFESP]
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• dARK ID: ark:/48912/00130000278s9
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo (UNIFESP)
• Palavras-chave em Português: Acute kidney injury; Cisplatin; Short chain fatty acids; Acetate; Inflammation; Lesão renal aguda; Cisplatina; Ácidos graxos de cadeia curta; Acetato; Inflamação
• Link de acesso: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=5762602; http://repositorio.unifesp.br/handle/11600/50624

Bacterial fermentation metabolites have increasingly been associated with systemic immune-inflammatory responses, besides their involvement in diseases such as cancer, obesity, diabetes and kidney damage. Recent evidence of a relationship between short chain fatty acids (SCFAs) and renal lesions suggests different roles of SCFAs as a therapeutic strategy for renal injury; however, their role in cisplatin-induced acute kidney injury (AKI) has not been determined. Cisplatin (CDDP) is an antineoplastic drug used in more than 500 treatment protocols for different types of cancer and its most common side effect is nephrotoxicity. Despite many efforts, no definitive treatment protocol can prevent cisplatin-induced AKI without affecting its antitumor properties. In this study, we evaluated the effect of acetate, a SCFA, as a possible protector of cisplatin-induced nephrotoxicity. We observed that acetate treatment reverses cisplatin-induced effects by preventing renal damage and decrease the level of urea, creatinine and Kim-1 in the serum. Transmission electron microscopy and Seahorse Analyzer showed that acetate prevents cisplatin-induced mitochondrial damage of renal tubule cells, restores the mitochondrial function by increasing the oxygen consumption rate (OCR), decreasing the extracellular acidification rate (ECAR) and the induction of reactive oxygen species (ROS) which results in the inhibition of cisplatin-induced cell death and AKI. The immune system plays a key role in the outcome and progression of cisplatin-induced AKI, we showed that acetate treatment prevents cisplatin-induced AKI infiltration of neutrophils and macrophages Ly6C+Ly6G- in the kidney. The macrophages CCR2 and CX3CR1 participate in the cisplatin-induced AKI while acetate treatment modulated these populations to a less inflammatory profile during renal injury. Our findings indicate that acetate ameliorates cisplatin-induced AKI both in vitro and in vivo, by a combinatory effect of preventing tubular cell death, and polarizing the macrophage-mediated inflammatory response.