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Doctoral Thesis
DOI
10.11606/T.42.2013.tde-12062013-103546
Document
Author
Full name
Lislaine Andrade Wensing
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2013
Supervisor
Committee
Campos, Alexandre Holthausen (President)
Gomes, Guiomar Nascimento
Magaldi, Antonio Jose Barros
Monte, Júlio Cesar Martins
Volpini, Rildo Aparecido
Title in Portuguese
Regulação do gene TBX3 por TGF-b1 em células mesangiais.
Keywords in Portuguese
Apoptose
Biologia celular
Biologia molecular
Expressão gênica
Glomérulos renais
Nefropatias
Abstract in Portuguese
As células mesangiais (CM) são essenciais para a homeostasia glomerular. Além disso, têm papel crucial no desenvolvimento de glomeroesclerose em nefropatias crônicas. Demonstramos que as isoformas do repressor de transcrição TBX3, TBX3.1 e TBX3 + 2a, foram suprarreguladas precocemente por concentrações baixas de TGF-b1 em CM humanas. A superexpressão das isoformas não alterou a proliferação ou produção de MEC em CM. Entretanto, diminuiu a apoptose induzida pela privação de SBF. Ademais, o silenciamento do gene TBX3 sensibilizou as CM ao estímulo pró-apoptótico causado pela remoção do SBF. Por fim, observamos aumento da expressão protéica de TBX3 nos glomérulos e túbulos em um modelo de nefropatia, guardando correlação temporal com o aumento dos níveis de TGF-b1, colágeno IV e fibronectina. Nossos resultados indicam que o gene TBX3 atua como um fator antiapoptótico nas CM e pode estar envolvido no mecanismo pelo qual TGF-b1 induz glomeruloesclerose e fibrose tubular durante a progressão das nefropatias.
Title in English
Regulation of TBX3 gene by TGF-b1 in mesangial cells.
Keywords in English
Apoptosis
Cell biology
Gene expression
Kidney glomerulus
Molecular biology
Nephropathies
Abstract in English
Mesangial cells (MC) are essential for glomerular homeostasis. In addition, MC play a significant role in the development of glomerulosclerosis of chronic nephropathies. We demonstrated that the transcription repressor TBX3 isoforms, TBX3.1 and TBX3 + 2a, were upregulated by low concentrations of TGF-b1. Selective overexpression of the isoforms did not affect MC proliferation or extracellular matrix production. However, TBX3 forced expression decreased apoptosis induced by FBS deprivation. Moreover, TBX3 gene silencing sensitized MC to the proapoptotic stimulus caused by SBF withdrawal. Finally, we observed an increase in TBX3 protein expression in glomerular and tubular regions in a model of chronic nephropathy (5/6 nephrectomy), temporally related to increased expression of TGF-b1, collagen IV and fibronectin. Our results indicate that TBX3 acts as an antiapoptotic factor in MC in vitro and may be involved in the mechanism by which TGF-b1 induces glomerulosclerosis and tubular fibrosis during the progression of nephropathies.
 
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Publishing Date
2013-09-05
 
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