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 Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: January 01, 2021
• End date: January 16, 2026
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Niels Olsen Saraiva Câmara
• Grantee: Magaiver Andrade Silva
• Host 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
• Associated scholarship(s): 22/12517-7 - Unrevealing the molecular pathways triggered by the accumulation of intracellular DNA and RNA in diabetic kidney disease patients and mouse models of fibrosis, BE.EP.PD

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.

Scientific publications

(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)

FORESTO-NETO, ORESTES; MENEZES-SILVA, LUISA; LEITE, JEFFERSON ANTONIO; ANDRADE-SILVA, MAGAIVER; CAMARA, NIELS OLSEN SARAIVA. Immunology of Kidney Disease. ANNUAL REVIEW OF IMMUNOLOGY, v. 42, p. 27-pg., 2024-01-01. (22/03740-4, 17/05264-7, 21/06748-3, 19/02893-9, 21/03192-4, 22/13289-8, 20/04592-3)

GONCALVES, LUIS EDUARDO D.; ANDRADE-SILVA, MAGAIVER; BASSO, PAULO JOSE; CAMARA, NIELS O. S.. Vitamin D and chronic kidney disease: Insights on lipid metabolism of tubular epithelial cell and macrophages in tubulointerstitial fibrosis. FRONTIERS IN PHYSIOLOGY, v. 14, p. 11-pg., 2023-03-29. (19/19435-3, 20/04592-3, 21/03182-9)