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Master's Dissertation
DOI
10.11606/D.5.2018.tde-06112018-133531
Document
Author
Full name
Fernanda Florencia Fregnan Zambom
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2018
Supervisor
Committee
Fujihara, Clarice Kazue (President)
Boim, Mirian Aparecida
Câmara, Niels Olsen Saraiva
Volpini, Rildo Aparecido
Title in Portuguese
A inibição das vias TLR4/NF-kB e do NLRP3/IL-1beta previne a DRC em um modelo de inibição crônica de NO associado à  sobrecarga de sal
Keywords in Portuguese
Hipertensão
Inflamassoma NLRP3
Insuficiência renal crônica
NF-kB
Óxido nítrico
Sobrecarga salina
Abstract in Portuguese
A inibição crônica do óxido nítrico com Nw-nitroargininemethylester (L-NAME), associado à sobrecarga de sal, leva a hipertensão grave, albuminúria, glomeruloesclerose, isquemia glomerular e fibrose intersticial, caracterizando um modelo de doença renal crônica (DRC). Achados anteriores deste laboratório e de outros sugerem que a ativação de pelo menos duas vias da imunidade inata, TLR4/NF-kB e NLRP3/IL-1beta, ocorre em vários modelos experimentais de DRC e que a progressão da lesão renal pode ser atenuada com a inibição destas vias. No presente estudo, investigamos se a ativação da imunidade inata, através da via TLR4/NF-kB ou NLRP3/IL-1beta, está envolvida na patogênese da lesão renal em outro modelo de DRC, o de inibição crônica do NO com sobrecarga de sal. Ratos Munich-Wistar machos adultos receberam sobrecarga de sal (2% Na+ na dieta e 0,5% Na+ na água do bebedouro) e L-NAME (32 mg/Kg/dia) dissolvido na salina do bebedouro (Grupo HS+N) ou tratados com alopurinol (Alo, 36 mg/Kg/dia, v.o), usado como inibidor de NLRP3 (grupo HS+N+Alo) ou tratados com ditiocarbamato de pirrolidina (PDTC, 60 mg/Kg/dia, v.o), um inibidor de NF-kB (Grupo HS+N+PDTC). Após 4 semanas, os ratos HS+N desenvolveram hipertensão arterial, albuminúria e lesão renal, juntamente com inflamação renal, estresse oxidativo e ativação de ambas as vias NLRP3/IL1-beta e TLR4/NF-kB. Alo reduziu o ácido úrico renal e inibiu a via NLRP3/IL-1beta. Esses efeitos foram associados à atenuação da hipertensão arterial, albuminúria e inflamação/fibrose intersticial, mas não à lesão glomerular. O PDTC diminuiu o ácido úrico renal e inibiu as vias NLRP3 e NF-kB, promovendo um efeito antiinflamatório e nefroprotetor mais eficiente que o Alo. As vias NLRP3/IL-1beta e TLR4/NF-kB atuam paralelamente para promover lesão/inflamação renal e devem ser simultaneamente inibidas para obter nefroproteção maior nesse modelo de DRC
Title in English
Inhibition of both the TLR4/NF-kB and NLRP3 inflammasome pathways prevents CKD in a model of chronic NO inhibition associated with salt overload
Keywords in English
Hypertension
NF-kB
Nitric oxide
NLRP3 inflammasome
Renal insufficiency chronic
Salt overload
Abstract in English
Nitric oxide inhibition with Nk-nitroargininemethylester (L-NAME) along with salt overload leads to severe hypertension, albuminuria, glomerulosclerosis, glomerular ischemia and collapse, together with interstitial fibrosis, characterizing a model of chronic kidney disease (CKD). Previous findings of this laboratory and elsewhere suggest that activation of at least two pathways of innate immunity, TLR4/NF-kB and NLRP3 inflammasome/IL-1beta, occurs in several experimental models of CKD, and that progression of renal injury can be slowed with inhibition of these pathways. In the present study, we investigated whether activation of innate immunity, through either the TLR4/NFkB or NLRP3/IL-1beta pathway, is involved in the pathogenesis of renal injury in yet another CKD model, chronic NO inhibition with salt overload. Adult male Munich-Wistar rats receiving L-NAME in drinking water and salt overload (Group HS+N) were treated with Allopurinol (ALLO), used as an NLRP3 inhibitor (Group HS+N+ALLO), or PyrrolidineDithiocarbamate (PDTC) a NF-kB inhibitor (Group HS+N+PDTC). After 4 wks, HS+N rats developed hypertension, albuminuria and renal injury, along with renal inflammation, oxidative stress and activation of both the NLRP3/IL1-beta and TLR4/NF-kB pathways. ALLO lowered renal uric acid and inhibited the NLRP3 pathway. These effects were associated with amelioration of hypertension, albuminuria and interstitial inflammation/fibrosis, but not glomerular injury. PDTC lowered renal uric acid and inhibited both the NLRP3 and NF-kB pathways, promoting a more efficient anti-inflammatory and nephroprotective effect than ALLO. NLRP3/IL-1beta and TLR4/NF-kB act in parallel to promote renal injury/inflammation and must be simultaneously inhibited for best nephroprotection
 
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Publishing Date
2018-11-08
 
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