Mechanisms of Trimethylamine-N-oxide (TMAO) in the progression of acute kidney injury in obesity.

• Grant number: 21/14553-8
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: January 01, 2022
• End date: January 31, 2023
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Alvaro Pacheco e Silva Filho
• Grantee: Camila Idelí Morales Fénero
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 17/05264-7 - Cell metabolism, microbiota and immune system: new paradigms in renal diseases physiopathology, AP.TEM

Abstract

In recent years, the intestinal microbiota has been the focus of attention due to its role in maintaining homeostasis and its participation in human pathologies. It is known that distant organs such as the kidney have a constant and bidirectional communication with the intestinal microbiota. Thus, both kidney diseases can affect the homeostasis of the microbiota, and metabolites produced by the microbiota can directly affect kidney function. Trimethylamine (TMA) is produced from the metabolism of choline, betaine and carnitine by the microbiota, and is absorbed by the intestine and metabolized in the liver by flavin-dependent monooxygenase 3 (FMO3) converting it to trimethylamine-N-oxide (TMAO). Recent studies have linked high plasma TMAO levels to an increased risk of cardiovascular disease, neurological disorders and chronic kidney disease. Studies in mice have shown that high-fat diets increase blood TMAO levels, causing renal interstitial fibrosis, increased phosphorylation of SMAD3, a key regulator of renal fibrosis, and increased expression of NADPH oxidase-4 (NOX4) in the kidney. Increased expression of KIM-1 and cystatin C in plasma was also observed. These kidney injury parameters have been associated with the presence of TMAO in the blood and possibly with the activation of oxidative stress pathways, but the exact mechanisms have not yet been identified. Zebrafish has been shown to be an excellent model for the study of microbiota and microbe-host interaction, as well as a model that is easy to genetically manipulate. Therefore, we propose to study the activation of the TMA/TMAO/oxidative stress pathway in the prognosis of cisplatin-induced acute kidney injury (AKI) using obese Danio rerio fish.