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Doctoral Thesis
DOI
10.11606/T.5.2018.tde-22102018-125017
Document
Author
Full name
Victor Ferreira de Avila
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2018
Supervisor
Committee
Fujihara, Clarice Kazue (President)
Abensur, Hugo
Girardi, Adriana Castello Costa
Oliveira, Rodrigo Bueno de
Title in Portuguese
Modelo de hipertensão arterial decorrente do bloqueio de NF-kB durante a nefrogênese: efeito da sobrecarga salina
Keywords in Portuguese
Doença renal crônica
Hipertensão
Inflamação
Nefropatias
NF-kappa B
Rim
Abstract in Portuguese
Recentemente descrevemos que ratos tratados com o inibidor do sistema NF-?B pirrolidina ditiocarbamato (PDTC) durante a lactação desenvolvem uma hipertensão arterial na fase adulta, sem lesão renal aparente, caracterizando assim um novo modelo hipertensão essencial. No presente estudo, nós investigamos se a Uninefrectomia (UNx) associada a uma sobrecarga salina (SS) na dieta revelaria uma possível disfunção renal, agravando assim a hipetensão arterial e levando a lesões renais. Ratos Munich-Wistar recém-nascidos foram divididos em 2 grupos: Controle, sem qualquer tratamento; e PDTCLact, recebendo PDTC (280 mg/Kg/dia) na água do bebedouro do 0 aos 20 dias após o nascimento. Após 10 semanas de vida, 120 ratos machos submetidos à Uninefrectomia e foram estudados em dois protocolos. No protocolo 1, os ratos machos foram subdivididos em: UNx+NS, ratos Controle recebendo dieta padrão (NS); PDTCLact+UNx+NS, ratos PDTCLact recebendo NS; UNx+SS, ratos Controle recebendo SS; PDTCLact+UNx+SS, ratos PDTCLact recebendo SS. Após 12 semanas, os animais do Grupo UNx+SS apresentaram hipertensão, aumento da albuminúria e lesões renais moderadas. Nos animais do grupo PDTCLact+UNx+SS a hipertensão, esclerose glomerular e a deposição de Colágeno-1 intersticial apresentaram um aumentado exacerbado, juntamente com lesões arteriolares do tipo "casca de cebola", estresse oxidativo, ativação do NF-kB, intenso infiltrado de macrófagos, linfócitos e aumento de células positivas para Angiotensina II, mesmo com a renina plasmática reduzida. Para investigar o papel do sistema renina-angiotensina neste modelo, no protocolo 2, 40 ratos foram divididos em: PDTCLact+UNx+SS, como descrito no protocolo 1; PDTCLact+UNx+SS+L, ratos tratados com Losartan (50 mg/kg) na água do bebedouro. O tratamento com Losartan foi capaz de atenuar as lesões glomerulares e a inflamação renal. Esses resultados indicam que a integridade do sistema NF-kB é fundamental para o desenvolvimento adequado do rim e a manutenção da homeostase do sódio na fase adulta. Paradoxalmente, esse mesmo sistema contribui para o desenvolvimento da lesão renal quando a disfunção renal causada por sua inibição durante a nefrogênese é desmascarada por UNx associada ao SS
Title in English
Salt overload aggravates hypertension and promotes severe renal injury in rats subjected to NF-?B inhibition during nephrogenesis
Keywords in English
Chronic kidney disease
Hypertension
Inflammation
Kidney
Nephropathy
NF-kappa B
Abstract in English
Recently we described that rats treated with the NF-?B inhibitor pyrrolidine dithiocarbamate (PDTC) during lactation develop high blood pressure hypertensive in adult life, without apparent functional or structural damage to the kidneys, thus providing a new model of essential hypertension. In the present study, we investigated whether uninephrectomy (UNx) associated with saline overload would unveil a possible renal dysfunction, thus aggravating arterial hypertension and leading to hemodynamically mediated renal injury. Munich-Wistar rat pups were divided into 2 groups: Control, receiving no treatment; and PDTCLact, receiving PDTC (280 mg/kg/ day) in the drinking water from 0 to 20 days after birth. At 10 weeks of age, 120 male rats underwent uninephrectomy and were studied in two protocols. In Protocol 1, rats were subdivided into: UNx+NS, control rats receiving normal salt (NS) diet; PDTCLact+UNx+NS, PDTCLact rats receiving NS; UNx+HS, control rats receiving high-salt (HS) diet; PDTCLact+UNx+HS, PDTCLact rats receiving HS. After 12 weeks, the UNx+HS animals were moderately hypertensive and exhibited mild albuminuria and renal injury. By contrast, arterial hypertension, glomerulosclerosis and cortical collagen-1 deposition were exacerbated in the PDTCLact+UNx+HS group, along with "onion skin" arteriolar lesions, evidence of oxidative stress, NF-kB activation and intense infiltration by macrophages, lymphocytes and angiotensin II-positive cells, even though circulating renin was depressed. To investigate the role of the renin-angiotensin system in this setting, 40 rats were divided into: PDTCLact+UNx+HS, treated as described before; and PDTCLact+UNx+HS+L, receiving in addition Losartan, 50 mg/kg in drinking water. Losartan treatment strongly atenuated glomerular injury and renal inflammation. The NF-kB system is essential for the kidneys to develop properly and maintain sodium homeostasis in adult life. Paradoxically, this same system contributes to renal injury when renal dysfunction caused by its inhibition during nephrogenesis is unmasked by UNx associated to HS
 
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Publishing Date
2018-10-23
 
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