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USE OF THE NLRP3 INHIBITOR ON INNATE IMMUNITY: EFFECT OF BRAIN DEATH AND COLD KIDNEY PRESERVATION

Grant number: 21/12637-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): July 01, 2022
Effective date (End): June 30, 2024
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal researcher:Mario Abbud Filho
Grantee:Naiane Do Nascimento Gonçalves
Home Institution: Faculdade de Medicina de São José do Rio Preto (FAMERP). Secretaria de Desenvolvimento Econômico (São Paulo - Estado). São José do Rio Preto , SP, Brazil

Abstract

Introduction: Brain death (BD) triggers systemic inflammation with consequent activation of inflammatory pathways in organs donated for transplants. Kidneys from deceased donors with extended criteria (ECD) or with high risk scores (KDPI > 85%) considered "non-ideal" kidneys could be used, but have been discarded by Tx teams for having inferior outcomes, worsening the shortage of organs for Tx. Prolonged cold ischemia time (CIT) may also be involved in changing the inflammatory profile of these kidneys. In a previous study we reported that molecules of the innate immunity pathways are more expressed in "non-ideal" kidneys than in kidneys from standard criteria donors (SCD). One of these highly expressed molecules is the inflammasome and based on this observation we hypothesized that blocking this protein complex could reduce the innate inflammatory response, alleviating sterile inflammation and improving the quality of "non-ideal" kidneys. Objectives: To evaluate the effect of NLRP3 inhibitor administration on gene and protein expression related to innate immunity and sterile inflammation, in rat kidneys, after the ME process and with prolonged cold ischemia time. Methods: Twenty-six male rats will be used, divided into 3 groups: sham rats (n=6), control rats with ME induction and without treatment (n=10); rats with induction of ME and administration of MCC950 (n=10) at the time of ME. After 6 hours of maintenance of mechanical ventilation, the animals kidneys will be perfused and preserved with Euro-Collins solution and analyzed at 12h and 24h of cold preservation. From the collected kidney samples, total RNA extraction will be performed for gene expression by real-time quantitative polymerase chain reaction (qPCR) using the TaqMan Gene Expression Array Plates system for molecules involved in the innate immune response, in addition to histological analysis and immunohistochemistry. Descriptive statistical analysis will include absolute and relative frequencies for categorical variables and means, medians, standard deviation and range for continuous variables. Comparison of groups of categorical variables will be performed using the chi-square test or Fisher's exact test, when appropriate. Values of P < 0.05 will be considered significant.

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