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Master's Dissertation
DOI
https://doi.org/10.11606/D.5.2020.tde-16062021-124022
Document
Author
Full name
Amanda Helen Albino
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2020
Supervisor
Committee
Zatz, Roberto (President)
Seguro, Antonio Carlos
Foresto Neto, Orestes
Oliveira, Rodrigo Bueno de
Title in Portuguese
Resposta imune inata na doença renal crônica que se segue à recuperação de uma lesão renal aguda induzida por gentamicina 
Keywords in Portuguese
Gentamicina
Imunidade inata
Inflamassoma NLRP3
Insuficiência renal crônica
Lesão renal aguda
NF-kappa B
Abstract in Portuguese
A alta incidência de Doença Renal Crônica (DRC) em pacientes que desenvolveram lesão renal aguda (LRA) indica que há uma tendência a desenvolver fibrose renal associada a eventos inflamatórios. Independentemente do insulto que desencadeou a LRA, a intensa necrose tubular promove a ativação de vias da imunidade inata, como a TLR4/NF-kB e a do inflamassomaNLRP3/IL-1beta. A gentamicina (GT), um antibiótico aminoglicosídeo de amplo espectro, induz LRA por um efeito nefrotóxico. Estudos anteriores sugerem que eventos inflamatórios contribuem para a transição LRA-DRC. No presente estudo, investigamos o comportamento das vias NLRP3 e NF-kB na progressão para DRC da LRA induzida por GT. Ratos machos Munich-Wistar adultos receberam injeção subcutânea de GT, 80 mg/kg/dia, durante 9 dias. Um grupo Controle (CN) recebeu apenas solução salina. Os animais foram examinados 1 (Dia 1), 30 (Dia 30) e 180 (Dia 180) dias após o tratamento com GT. No Dia 1, os ratos GT exibiram albuminúria acentuada e retenção de creatinina, alterações na fração de excreção de Na+ e K+, necrose tubular aguda (NTA) com aumento da abundância renal de KIM-1, lesões glomerulares, inflamação intersticial e ativação das vias TLR4/NF-kB eNLRP3/IL-1beta. No Dia 30, a NTA regrediu e houve recuperação da função renal, mas a deposição cortical de colágeno-1 e fibronectina se manteve, em associação com a presença de células AngII+ e da ativação do sistema NF-kB. No Dia 180, os ratos voltaram a apresentar albuminúria e lesões glomerulares como esclerose segmentar e colapso do tufo, enquanto a fibrose intersticial se manteve. Essas alterações associaramse novamente à presença de células AngII+, indicativa de ativação local do sistema reninaangiotensina, e à ativação do sistema NF-kB. Essas alterações podem mediar a transição de LRA a DRC após tratamento com GT
Title in English
Innate immune response on CKD recover after acute renal injury induced by gentamicin
Keywords in English
Acute kidney injury
Chronic renal insufficiency
Gentamicin
Immunity innate
Inflamassome NLRP3
NF-kappa B
Abstract in English
The slow development of Chronic Kidney Disease (CKD) is a common outcome in patients recovering from acute kidney injury (AKI). The mechanisms underlying this complication are not fully understood and may involve the development of inflammation. Regardless of the initial insult, the intense tubular necrosis activates innate immunity pathways, such as TLR4/NF-?B and the NLRP3/IL-1beta inflammasome. Gentamicin (GT), a broad-spectrum aminoglycoside antibiotic, induces AKI by a nephrotoxic effect. Previous evidence suggests that inflammation contributes to the AKI-CKD transition. In the present study, we investigated the behavior of the NLRP3 and NF-kB pathways in the progression of CKDinduced AKI to GT. Adult male Munich-Wistar rats received subcutaneous injection of GT, 80 mg/kg/day, for 9 days. A control group (CN) received saline only. Animals were examined 1 (Day 1), 30 (Day 30) and 180 (Day 180) days after treatment with GT. On Day 1, GT rats exhibited marked albuminuria and creatinine retention, changes in the Na+ and K+ excretion fraction, acute tubular necrosis (ATN) with increased renal abundance of KIM-1, glomerular lesions, interstitial inflammation and activation of the TLR4/NF-kB and NLRP3/IL-1k pathways. On Day 30, ATN regressed and renal function was restored, but the cortical deposition of collagen-1 and fibronectin persisted, in association with the presence of AngII+ cells and NF-kB activation. On Day 180, albuminuria, and glomerular lesions such as segmental sclerosis and tuft collapse relapsed, along with persistence of interstitial fibrosis. These changes were again associated with the presence of AngII + cells, indicative of local activation of the renin-angiotensin system, and with the activation of the NF-kB system. These abnormalities can mediate the transition from GT-induced AKI to CKD
 
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Publishing Date
2021-06-23
 
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