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DNA repair, metabolism and the inflammatory immune response triggered by ischemia and reperfusion injury

Grant number: 19/15166-8
Support Opportunities:Scholarships in Brazil - Post-Doctorate
Effective date (Start): March 01, 2020
Effective date (End): January 31, 2021
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Niels Olsen Saraiva Câmara
Grantee:Camila Pontes Ferreira
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

Abstract

The acute renal injury (AKI) is one of the major public health problems in the world. In South America, the incidence of AKI is 31% and in Brazil 5% of the cases correspond to hospitalization and 30% of hospitalizations in the Intensive Care Unit (ICU). One of the causes of AKI is renal Ischemia and Reperfusion Injury (IRI), which is induced by impairment in the delivery of oxygen, nutrients and accumulation of toxic insults in the kidneys, and this imbalance leads to injury to the epithelial cells and consequently cell death by apoptosis and necrosis. During the processes of apoptosis and necrosis there is production of Reactive Oxygen Species (ROS) and the accumulation of these substances causes deleterious effects on the cells as DNA damage, that can modify the composition and structures of the nitrogenous bases, besides generating breaks in the DNA of the nucleus and mitochondria. To ensure DNA integrity, DNA repair systems are activated, among them, nucleotide excision (NER), base excision (BER) repair systems. These mechanisms can be activated against products generated by ROS, which are abundant in IRI. ROS modulates the metabolism of CD4 T cells and activated macrophages leading to the production and/or inhibition of cytokines, changes in their differentiation and metabolism. Defects in the NER pathway are associated with human hereditary diseases such as Xeroderma Pigmentosum (XP) and patients with XP has impairment in the cellular immune response. Has been demonstrated that DNA damage are able to induce the production of pro-inflammatory and regulatory cytokines such as TNF, IL-6 and IL-10. Since during IRI there is inflammation and in these sites of inflammation the T lymphocytes are in contact with high concentrations of reactive species of oxygen we hypothesize that DNA damages caused by ROS influence in the metabolism and consequently in the immune response of CD4+ T lymphocytes, which are the main cells who causes damage during the AKI. To performed that, we'll work with several experimental approaches, using genetically modified animals with the deletion of XPA and XPC genes, cellular metabolism measurements, protein and genetic expression analysis, renal tissue morphometry and functional cellular and tissue analysis to answer the proposed objectives. The IRI will be performed by bilateral clamping of the renal pedicles, already well established in the laboratory. We hope to demonstrate that in the absence of repair mechanisms, the inflammatory response is exacerbated and, therefore, the outcome of the renal injury will be worse. We believe that part of this exacerbated inflammatory response may be due to alterations in the cellular mechanism, thus connecting DNA repair to classic metabolic pathways. (AU)

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