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The role of the intracellular DNA sensor, AIM2, and signaling molecules, STING and MAVS, in proximal tubular epithelial cell metabolism in kidney fibrosis development

Grant number: 20/04592-3
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): January 01, 2021
Effective date (End): December 31, 2022
Field of knowledge:Health Sciences - Medicine
Principal researcher:Niels Olsen Saraiva Câmara
Grantee:Magaiver Andrade Silva
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). 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

Renal fibrosis is a common hallmark of chronic kidney disease (CKD) and major determinant of progressive renal function loss, leading to the need for dialysis or transplantation. Recently, studies have shown that during fibrogenesis occur a metabolic reprogramming in tubular epithelial cell (TEC) that affects its phenotype and function, culminating in renal fibrosis. The mechanisms that orchestrate this process are still poorly understood, which makes it impossible to develop effective strategies for the CKD treatment. Nucleic acids, DNA and RNA, are recognized by cytoplasmic sensors and trigger an inflammatory response when released from their organelles during cellular stress, acting as damage-associated molecular patterns. Previous studies correlate elevated levels of mitochondrial DNA (in the circulation and urine) with chronic inflammation in renal patients undergoing hemodialysis and with CKD prognosis. Considering the clinical importance, it is essential to understand the nucleic acids signaling and its interface with kidney fibrosis. AIM2 is a DNA sensor and the molecules, STING and MAVS are activated after the DNA recognition by cGAS and RNA by RIG-I, respectively. Thus, we hypothesize that activation of these molecules alone or in cooperation influences the CETs metabolism and it is a point that link inflammation and kidney fibrosis development. Therefore, we aim in this project to understand the interface between nucleic acid signaling and CET metabolism in the kidney fibrosis. Our preliminary results in vivo and in vitro demonstrated that AIM2 activation modulates metabolic genes expression, concomitant with the increase in the pro-fibrotic genes in a renal fibrosis mice model and in CETs stimulated with synthetic DNA. We are confident that the results of this project will reveal new targets for the CKD treatment and will support other studies about the CKD pathophysiology.