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Factores de risco na insuficiência renal crónica: estudo de factores genéticos e bioquímicos que possam contribuir para a patologia: relações com os sistemas de defesa antioxidante e imunitário
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Resumo(s)
O objectivo deste trabalho consistiu em estudar a participação da sobrecarga oxidante e da resposta inflamatória na insuficiência renal crónica (IRC). Determinaram-se concentrações plasmáticas de citocinas e moléculas de adesão na patologia e do NO, glutationo, homocisteína, ferro, ferritina e ácido úrico em controlos e doentes. As actividades enzimática do sintase do NO (eNOS), redutase da metahemoglobina (MTHbR), oxidorredutase dependente do NADH e fosfatase ácida foram avaliadas nestas populações. Os polimorfismos do eNOS, mieloperoxidase, redutase do metilenotetrahidrofolato e da haptoglobina foram estudados como possíveis factores de susceptibilidade genética. Verificou-se uma diminuição da razão GSH/GSSG e da actividade do oxidorredutase transmembranar associada a um aumento da MTHbR, demonstrando a presença de sobrecarga oxidante na patologia. Elevadas concentrações de citocinas e moléculas de adesão associaram um processo de inflamação crónica à IRC. Foram verificadas diferentes correlações entre a sobrecarga oxidante e a resposta inflamatória nomeadamente, entre nitrotirosina, IL-6 e sVCAM-1. Esta relação pode ser igualmente associada a um aumento da concentração plasmática de homocisteína e sua correlação com a ferritina sérica (um marcador de Fe livre). A fosfatase ácida apresentou uma correlação negativa com a concentração plasmática de nitrato, o que poderá indicar uma possível inibição do enzima pelo NO. Relativamente aos polimorfismos genéticos somente a haptoglobina aparenta ser um indicador de predisposição para a patologia, dada a maior prevalência do fenótipo Hp2-2 na patologia. Assim, foi possível concluir-se que existem várias possíveis causas envolvidas na etiologia e progressão da insuficiência renal crónica. O valor experimental deste conhecimento poderá ter implicações práticas na descoberta de novos alvos e terapêuticas para a IRC.
The objective of this work was to study the influence of oxidative stress and inflammatory response in chronic renal failure (CRF). Serum concentrations of cytokines and adhesion molecules were quantified in this pathology. Determnations of NO, glutathione, homocysteine, iron, ferritin and uric acid were done in control and disease groups. The enzyme activities of eNOS, methemoglobin redutase, transmembrane oxidoreductase and acid phosphatase were measured in the same population. The polymorphisms of eNOS, myeloperoxidase, methylenetetrahydrofolate reductase and haptoglobin were studied has possible genetic factors for CRF predisposition. A decrease in GSH/GSSG ratio and transmembrane oxidoreductase activity was observed, in addition with an increase in methemoglobin reductase, demonstranting the presence of oxidative stress in the pathology. The elevated serum concentrations of cytokines and adhesion molecules in CRF individuals related chronic inflammatory response to the pathology. Correlations were obtained between oxidative stress and inflammatory response, namely between nitrotyrosine, IL-6 and sVCAM-1. This relation may be associated with an increase in plasma homocysteine levels and its correlation with serum ferritin (a free iron marker). There was a negative correlation between acid phosphatase and serum nitrate levels, which imply an enzyme inhibition by NO. The results obtained for the genetic polymorphisms studied showed that only haptoglobin might be useful has a genetic marker of CRF, due to the higher prevalence of phenotype Hp2-2 in the pathology. In this study it was possible to conclude that there are several possible causes involved in the etiology and progression of chronic renal failure. The experimental value of such knowledge may have practical implications in the discovery of new targets and therapeutics for CRF.
The objective of this work was to study the influence of oxidative stress and inflammatory response in chronic renal failure (CRF). Serum concentrations of cytokines and adhesion molecules were quantified in this pathology. Determnations of NO, glutathione, homocysteine, iron, ferritin and uric acid were done in control and disease groups. The enzyme activities of eNOS, methemoglobin redutase, transmembrane oxidoreductase and acid phosphatase were measured in the same population. The polymorphisms of eNOS, myeloperoxidase, methylenetetrahydrofolate reductase and haptoglobin were studied has possible genetic factors for CRF predisposition. A decrease in GSH/GSSG ratio and transmembrane oxidoreductase activity was observed, in addition with an increase in methemoglobin reductase, demonstranting the presence of oxidative stress in the pathology. The elevated serum concentrations of cytokines and adhesion molecules in CRF individuals related chronic inflammatory response to the pathology. Correlations were obtained between oxidative stress and inflammatory response, namely between nitrotyrosine, IL-6 and sVCAM-1. This relation may be associated with an increase in plasma homocysteine levels and its correlation with serum ferritin (a free iron marker). There was a negative correlation between acid phosphatase and serum nitrate levels, which imply an enzyme inhibition by NO. The results obtained for the genetic polymorphisms studied showed that only haptoglobin might be useful has a genetic marker of CRF, due to the higher prevalence of phenotype Hp2-2 in the pathology. In this study it was possible to conclude that there are several possible causes involved in the etiology and progression of chronic renal failure. The experimental value of such knowledge may have practical implications in the discovery of new targets and therapeutics for CRF.
Descrição
Tese de mestrado, Bioquímica, Universidade de Lisboa, Faculdade de Ciências, 2009
Palavras-chave
Insuficiência renal crónica Sobrecarga oxidante Resposta inflamatória Polimorfismos genéticos Teses de mestrado - 2009