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J Am Soc Nephrol ; 19(11): 2108-18, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18667730

RESUMO

Accumulating evidence suggests that upregulation of cyclooxygenase 2 (COX2) in glomerular podocytes promotes podocyte injury. Because Gq signaling activates calcineurin and calcineurin-dependent mechanisms are known to mediate COX2 expression, this study investigated the role of Gqalpha in promoting COX2 expression in podocytes. A constitutively active Gq alpha subunit tagged with the TAT HIV protein sequence was introduced into an immortalized podocyte cell line by protein transduction. This stimulated inositol trisphosphate production, activated an nuclear factor of activated T cells-responsive reporter construct, and enhanced levels of both COX2 mRNA and protein compared with cells treated with a Gq protein lacking the TAT sequence. Induction of COX2 was associated with increased prostaglandin E(2) production and podocyte death, both of which were attenuated by selective COX2 inhibition. In vivo, levels of COX2 mRNA and protein were significantly enhanced in podocytes from transgenic mice that expressed podocyte-targeted constitutively active Gqalpha compared with nontransgenic littermates. These data suggest that Gq-dependent signaling cascades stimulate calcineurin and, in turn, upregulate COX2 mRNA and protein, increase eicosanoid production, and cause podocyte injury.


Assuntos
Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Podócitos/metabolismo , Animais , Sequência de Bases , Calcineurina/metabolismo , Morte Celular , Linhagem Celular , DNA Complementar/genética , Dinoprostona/biossíntese , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Inositol 1,4,5-Trifosfato/biossíntese , Camundongos , Camundongos Transgênicos , Fatores de Transcrição NFATC/metabolismo , Podócitos/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transdução de Sinais , Regulação para Cima , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética
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