Alterações histofisiológicas induzidas pela inibição de HIF em animais tratados com Luteolin
Data
2024-09-04
Autores
Mendonça Junior, Bolival Apparecido 
Orientadores
Columbari, Eduardo
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
O fator induzido por hipóxia (HIF) é expresso em todos os tecidos do corpo e modula respostas transcricionais frente ao estímulo hipóxico; em normoxia, o HIF é hidroxilado por prolilhidroxilases (PHDs) e fator de inibição de HIF (FIH). O HIF tem se mostrado como um importante regulador da homeostase de O2 podendo controlar a expressão de vários genes, bem como respostas fisiológicas frente a situações de hipóxia presentes em várias doenças, o HIF é um alvo da pesquisa farmacológica, e dentre as substâncias exploradas temos o luteolim, um flavonóide, com capacidade de interferir na ação de HIF. Buscamos investigar se tratamento por 7 dias com luteolim (10μg/kg) em animais saudáveis submetidos ou não a hipóxia intermitente crônica, para aumento da expressão de HIF, foi capaz de reduzir a resposta ventilatória a hipóxia e causar alterações no rim e aorta. Também observamos redução na sensibilidade do corpúsculo carotídeo devido a administração aguda de Luteolim e se isto impactaria em alterações ventilatórias. Em situações de normoxia, o tratamento com LUT foi capaz de diminuir as espécies reativas de nitrogênio, no tronco encefálico e no rim, e causar uma redução de mRNA para HIF-1α no tronco e em neurônios imunomarcados para HIF-1α no NTS-c além de redução de imunomarcação para HIF-1α e HIF-2α no rim em HIC. Em conjunto estes resultados apontam que o tratamento com o LUT foi capaz de causar uma redução em espécies reativas de nitrogênio nesses órgãos, possivelmente o estresse oxidativo, e foi capaz de alterar a expressão dos fatores de transcrição induzidos por hipóxia (HIF-1α e HIF-2α). A modulação destes fatores causou as alterações morfológicas observadas no rim e na aorta, como: aumento de conteúdo de colágeno na capsula glomerular e na túnica media da aorta; Alterações na musculatura lisa da aorta e nas lamelas elásticas; Assim como aumento do espaço glomerular e aumento do diâmetro do capilar glomerular. As alterações observadas podem ser decorrentes da inibição da via de geração de espécies reativas de nitrogênio, e da ação indireta do LUT a atividade de transcrição do HIF. O uso prolongado de Luteolim em situações não patológicas demonstra danos estruturais no rim e aorta em situações de hipóxia ou normoxia possivelmente devido a inibição de HIF-1α e HIF-2α. Além disso, o tratamento prolongado causa a redução da resposta ventilatória a hipóxia, e da sensibilidade do corpúsculo carotídeo a hipóxia aguda. Apesar de ser um antioxidante, não conseguiu reduzir o estresse oxidativo no tronco encefálico durante HIC. Desta forma seu uso deve ser planejado de acordo com cada caso clinico.
Hypoxiainducible factor (HIF) is expressed in all body tissues and modulates transcriptional responses to hypoxic stimuli; in normoxia, HIF is hydroxylated by prolyl hydroxylases (PHDs) and HIF inhibitory factor (FIH). HIF has been shown to be an important regulator of O2 homeostasis, capable of controlling the expression of various genes as well as physiological responses to hypoxic conditions present in various pathologies. HIF is a target of pharmacological research, and among the substances explored is luteolin, a flavonoid, with the ability to interfere with HIF action. We sought to investigate whether 7day treatment with luteolin (10μg/kg) in healthy animals subjected or not to chronic intermittent hypoxia, to increase HIF expression, was able to reduce the ventilatory response to hypoxia and cause changes in the kidney and aorta. We also observed a reduction in carotid body sensitivity due to acute administration of luteolin and whether this would impact ventilatory changes. In normoxic conditions, treatment with LUT was able to decrease reactive nitrogen species in the brainstem and kidney, and cause a reduction in mRNA for HIF1α in the brainstem and in neurons immunolabeled for HIF1α in the NTSc, as well as a reduction in immunolabeling for HIF1α and HIF2α in the kidney in HIC. Together, these results indicate that treatment with LUT was able to cause a reduction in reactive nitrogen species in these organs, possibly oxidative stress, and was able to alter the expression of hypoxiainducible transcription factors (HIF1α and HIF2α). The modulation of these factors caused the morphological changes observed in the kidney and aorta, such as: increased collagen content in the glomerular capsule and the tunica media of the aorta; changes in the smooth muscle of the aorta and elastic lamellae; as well as increased glomerular space and increased diameter of the glomerular capillary. The observed changes may result from the inhibition of the reactive nitrogen species generation pathway and the indirect action of LUT on HIF transcription activity. Prolonged use of luteolin in nonpathological situations demonstrates structural damage to the kidney and aorta in hypoxic or normoxic conditions, possibly due to inhibition of HIF1α and HIF2α. Additionally, prolonged treatment causes a reduction in the ventilatory response to hypoxia and the sensitivity of the carotid body to acute hypoxia. Despite being an antioxidant, it was unable to reduce oxidative stress in the brainstem during HIC. Therefore, its use should be planned according to each clinical case.
Hypoxiainducible factor (HIF) is expressed in all body tissues and modulates transcriptional responses to hypoxic stimuli; in normoxia, HIF is hydroxylated by prolyl hydroxylases (PHDs) and HIF inhibitory factor (FIH). HIF has been shown to be an important regulator of O2 homeostasis, capable of controlling the expression of various genes as well as physiological responses to hypoxic conditions present in various pathologies. HIF is a target of pharmacological research, and among the substances explored is luteolin, a flavonoid, with the ability to interfere with HIF action. We sought to investigate whether 7day treatment with luteolin (10μg/kg) in healthy animals subjected or not to chronic intermittent hypoxia, to increase HIF expression, was able to reduce the ventilatory response to hypoxia and cause changes in the kidney and aorta. We also observed a reduction in carotid body sensitivity due to acute administration of luteolin and whether this would impact ventilatory changes. In normoxic conditions, treatment with LUT was able to decrease reactive nitrogen species in the brainstem and kidney, and cause a reduction in mRNA for HIF1α in the brainstem and in neurons immunolabeled for HIF1α in the NTSc, as well as a reduction in immunolabeling for HIF1α and HIF2α in the kidney in HIC. Together, these results indicate that treatment with LUT was able to cause a reduction in reactive nitrogen species in these organs, possibly oxidative stress, and was able to alter the expression of hypoxiainducible transcription factors (HIF1α and HIF2α). The modulation of these factors caused the morphological changes observed in the kidney and aorta, such as: increased collagen content in the glomerular capsule and the tunica media of the aorta; changes in the smooth muscle of the aorta and elastic lamellae; as well as increased glomerular space and increased diameter of the glomerular capillary. The observed changes may result from the inhibition of the reactive nitrogen species generation pathway and the indirect action of LUT on HIF transcription activity. Prolonged use of luteolin in nonpathological situations demonstrates structural damage to the kidney and aorta in hypoxic or normoxic conditions, possibly due to inhibition of HIF1α and HIF2α. Additionally, prolonged treatment causes a reduction in the ventilatory response to hypoxia and the sensitivity of the carotid body to acute hypoxia. Despite being an antioxidant, it was unable to reduce oxidative stress in the brainstem during HIC. Therefore, its use should be planned according to each clinical case.
Descrição
Citação
MENDONÇA JUNIOR, Bolival Apparecido. Alterações histofisiológicas induzidas pela inibição de HIF em animais tratados com Luteolin. 2024. 73 f. Tese (Doutorado em Farmacologia) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP). São Pailo, 2024.