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    Therapeutic approaches to minimise acute renal failure in an animal model of myoglobinuria (2013)

    Art
    Hochschulschrift
    Autor
    Gröbler, Ludwig K. (WE 12)
    Quelle
    Berlin: Mensch und Buch Verlag, 2013 — IV, 85 Seiten
    ISBN: 978-3-86387-276-2
    Sprache
    Englisch
    Verweise
    URL (Volltext): http://www.diss.fu-berlin.de/diss/receive/FUDISS_thesis_000000093833
    Kontakt
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    +49 30 838 62450

    Abstract / Zusammenfassung

    Burns are one of the main causes leading to lethal acute renal failure (ARF).
    Coagulative necrosis of the skin and the underlying subcutaneous tissue including muscle cells, a process termed RM (rhabdomyolysis), leads to the release of toxic factors including extracellular skeletal myoglobin (Mb). If its amount in the circulation exceeds the binding capacity of the protein haptoglobin, Mb is filtered by the glomeruli and is secreted in the urine, a condition termed myoglobinuria.
    Accumulating Mb can damage the kidneys by intrarenal vasoconstriction, direct and ischemic tubule injury and tubular obstruction. However, the exact mechanisms are yet unclear. It has been proposed that the release of free iron from the heme group can generate hydroxyl radicals and cause cellular injury. In addition, extracellular myoglobin can undergo redox cycling to yield ferric Mb and from then to the pro-oxidative ferryl state. The ferryl form can initiate lipid peroxidation and renal injury without invoking release of free iron. Furthermore, Mb is a pro-oxidant and initiates the oxidation of biological targets including cell membranes, proteins and DNA.
    This study tested whether chelators or antioxidants are able to ameliorate ARF through inhibiting oxidative stress. In a cell model using cultured kidney epithelial cells the chelators inhibited Mb-induced oxidative stress and inflammation and improved epithelial cell function. The new iron chelator DFOB-AdAOH showed similar activity to DFOB and due to its low toxicity may be a promising candidate in the treatment of iron overload disease as well as a potential therapeutic strategy to combat ARF after RM.
    In an animal model of RM, co-supplementation with tetra-tert-butyl bisphenol (BP) and vitamin C (Vit C) or both BP and Vit C inhibited lipid peroxidation and inflammation but only Vit C, when administered alone, improved renal function as monitored by selected markers of AKF. These data indicate that lipid- and water-soluble antioxidants may differ in terms of their therapeutic impact on RM-induced renal dysfunction.
    However, the lack of correlation between antioxidant activity and biomarkers of renal dysfunction makes it difficult to evaluate renal damage. Although oxidative stress has an evidential role in ARF, it seems to be a combination of several factors that include, but are not limited to, cytokines released during RM, shock, dehydration and acidosis. Therefore, a therapeutic intervention should aim to restore glomerular filtration rate, increase blood flow to the glomerulus, and inhibit tubular obstruction by Mb casts. Finally, our studies indicate that further work with the chelator DFOB-AdaOH is warranted. Thus, whether DFOB-AdaOH diminishes oxidative stress caused by both free iron and Mb pro-oxidant activity and whether this can protect the kidneys from experimental ARF should be evaluated further using in vivo models in the future.