Interface between DNA repair mechanisms and metabolism in the regulation of differentiation and function of CD4+ T cells

Abstract

Acute kidney injury (AKI) is one of the biggest public health problems worldwide, and in South America the reported incidence is 31%, and, in Brazil, it corresponds to 5% of hospitalizations and 30% of admissions to an intensive care unit. Intensive Care (ICU). One of the causes of AKI is ischemia and reperfusion injury (IRI) which is induced by impaired delivery of oxygen and nutrients, as well as the accumulation of toxic products in the kidneys. These changes induce lesions in epithelial cells and, consequently, cell death by apoptosis and necrosis. During the processes of apoptosis and necrosis, reactive oxygen species (ROS) are produced, which can cause deleterious effects on cells in the microenvironment, such as DNA damage, modifying the structures of nitrogenous bases, in addition to generating breaks. in nuclear and mitochondrial DNA. To ensure DNA integrity, DNA repair systems are activated, including nucleotide excision repair (NER) and base excision repair (BER) systems. These mechanisms can be activated against products generated by ROS, which are abundant in IRI. ROS modulate the metabolism of CD4+ T lymphocytes, which in turn influence the production of cytokines, as well as differentiation. Defects in the NER pathway are associated with hereditary human diseases such as Xeroderma Pigmentosum (XP) and patients with XP have impaired immune responses. It has already been shown that DNA damage modulates the immune response of T cells, also influencing the production of pro-inflammatory and regulatory cytokines such as: TNF, IL-6 and IL-10. Considering that inflammation occurs during IRI and that at these sites T lymphocytes are in contact with high concentrations of ROS, we hypothesized that DNA damage caused by ROS influences metabolism and, consequently, the immune response of T lymphocytes. CD4+. For this, we will work with several experimental approaches, including the use of genetically modified animals with the deletion of XPA and XPC genes, as well as functional evaluations and cellular metabolism, gene and protein expression and kidney tissue morphometry to respond to 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 kidney injury will be worse. We believe that part of this exacerbated inflammatory response may be due to changes in the cellular mechanism, thus connecting DNA damage repair to classical metabolic pathways. (AU)