Role of iNOS in the renal alterations induced by experimental sepsis in rats chronically treated with ethanol

• Grant number: 18/06583-1
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): July 01, 2018
• Effective date (End): June 30, 2020
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Carlos Renato Tirapelli
• Grantee: Arthur Henrique de Sousa
• Host Institution: Escola de Enfermagem de Ribeirão Preto (EERP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Sepsis is defined as an organ dysfunction, with a potential risk of death, caused by a dysregulated host response to an infection. Sepsis leads to impaired renal function due to changes in the glomerular structure and a local inflammatory process. The experimental model of cecal ligation and puncture (CLC) is considered the most similar to human sepsis and has been widely used in the study of mechanisms by which sepsis affects renal function. The results of these experimental studies show that sepsis induces damage to renal function leading to increased plasma concentrations of urea and creatinine. These studies also show that induction of the enzyme inducible nitric oxide (NO) synthase (iNOS) is an important mechanism by which sepsis induces its effects in the kidney. In addition, sepsis induces increased generation of reactive oxygen species (ROS) and this response may lead to lipoperoxidation, protein nitration and tissue dysfunction. Individuals who consume ethanol frequently and who develop sepsis present longer hospitalization and higher mortality rates. In addition, chronic consumption of ethanol alters the renal function emerging as an important risk factor for the development of nephropathies. In the kidney, the chronic consumption of ethanol induces the expression of iNOS, increases the generation of ROS, and these actions lead to tissue damages that result in functional alterations. Therefore, both sepsis and ethanol consumption have a relevant impact on renal structure and function, and iNOS stands out as an important element that mediates these responses. However, there are no studies evaluating the impact of ethanol consumption on sepsis-induced renal changes or the mechanisms involved in this response. The hypothesis of this study is that chronic ethanol consumption will induce increased iNOS expression in the kidney, and this response will cause important renal changes that will contribute to the worsening of sepsis. In addition to the induction of iNOS, increased production of ROS would be another signaling pathway activated by ethanol that would lead to tissue damage by lipoperoxidation and nitration, thus contributing to increased renal dysfunction and susceptibility to sepsis. Although it has been reported that chronic ethanol consumption contributes to the worsening of sepsis, there are no studies describing whether renal damage caused by ethanol consumption is important in this process. Therefore, the present project was designed to investigate the impact of ethanol consumption on renal damage induced by sepsis and the possible participation of iNOS in these responses.

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)

SOUSA, ARTHUR H.; DO VALE, GABRIEL T.; NASCIMENTO, JOSE A.; AWATA, WANESSA M. C.; SILVA, CARLA B. P.; ASSIS, VICTOR O.; ALVES, V, JULIANO; TOSTES, RITA C.; TIRAPELLI, CARLOS R.. Inhibition of inducible nitric oxide synthase protects against the deleterious effects of sub-lethal sepsis and ethanol in the cardiorenal system. Canadian Journal of Physiology and Pharmacology, v. 99, n. 12, p. 1324-1332, DEC 2021. (17/24123-5, 18/06583-1, 18/23985-6)