Publication: Cilastina en la prevención y tratamiento del fracaso renal agudo parenquimatoso de origen endotóxico : sepsis y rabdomiólisis
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2022-11-04
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Universidad Complutense de Madrid
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Abstract
El fracaso renal agudo (FRA) parenquimatoso se define como un síndrome clínico secundario a múltiples causas en el que tiene lugar un deterioro brusco de las funciones renales, alterando la homeostasis y la composición del medio interno. La sepsis y la rabdomiólisis son dos síndromes complejos, que se incluyen como causas dentro del FRA parenquimatoso endotóxico debido a que el daño es producido por moléculas endógenas derivadas de los mismos, como son el lipopolisacárido (LPS) y la mioglobina que se comportan como endotoxinas. Ambos producen daño por vasoconstricción renal, inflamación, estrés oxidativo, muerte celular y obstrucción tubular. Actualmente no existe ningún fármaco específico para la prevención o el tratamiento del FRA, por lo que la búsqueda de novedosas estrategias protectoras es una tarea prioritaria. Cilastatina, un inhibidor competitivo de la enzima renal de hidropeptidasa-I (DHP-I) localizada en las balsas de colesterol (BDC) de las células epiteliales del túbulo proximal, ha demostrado tener un efecto protector en estudios previos de nuestro grupo. En modelos de FRA inducido por diferentes nefrotóxicos de uso común en clínica, el efecto protector de cilastatina era debido en parte a la interferencia con las BDC, que reducía o cancelaba pasos claves de la señalización auto y paracrina de la ruta extrínseca de la apoptosis...
Parenchymal acute renal failure (ARF) is defined as a clinical entity secondary to multiple causes in which an abrupt deterioration of renal functions alters homeostasis and the composition of the internal environment. Sepsis and rhabdomyolysis are two complex syndromes that causes endotoxic parenchymal ARF due to the presence of lipopolysaccharide (LPS) and myoglobin respectively, which act as endotoxins. Both produce damage by inducing renal vasoconstriction, inflammation, oxidative stress, cell death and tubular obstruction. There is currently no specific drug for the prevention or treatment of ARF in the context of sepsis and rhabdomyolysis so, the search for novel protective strategies with Clinical application is a priority task. In previous studies by our group that cilastatin, a competitive inhibitor of the renal dehydropeptidase-I (DHP-I) enzyme located in the cholesterol rafts (CR) of proximal tubule epithelial cells, protects renal tubule from damage. In models of ARF induced by different compounds commonly used in the clinic with nephrotoxic properties, the protective effect of cilastatin was due in part to interference with the CR, which either reduced or halted key steps in the auto- and paracrine signaling of the extrinsic pathway of apoptosis...
Parenchymal acute renal failure (ARF) is defined as a clinical entity secondary to multiple causes in which an abrupt deterioration of renal functions alters homeostasis and the composition of the internal environment. Sepsis and rhabdomyolysis are two complex syndromes that causes endotoxic parenchymal ARF due to the presence of lipopolysaccharide (LPS) and myoglobin respectively, which act as endotoxins. Both produce damage by inducing renal vasoconstriction, inflammation, oxidative stress, cell death and tubular obstruction. There is currently no specific drug for the prevention or treatment of ARF in the context of sepsis and rhabdomyolysis so, the search for novel protective strategies with Clinical application is a priority task. In previous studies by our group that cilastatin, a competitive inhibitor of the renal dehydropeptidase-I (DHP-I) enzyme located in the cholesterol rafts (CR) of proximal tubule epithelial cells, protects renal tubule from damage. In models of ARF induced by different compounds commonly used in the clinic with nephrotoxic properties, the protective effect of cilastatin was due in part to interference with the CR, which either reduced or halted key steps in the auto- and paracrine signaling of the extrinsic pathway of apoptosis...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Biológicas, leída el 27-04-2022