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Introduction: Severe rhabdomyolysis (RM) is a complication leading to myoglobinuria, with up to 20% of burns patients developing acute kidney injury (AKI). Although the causal mechanisms are poorly understood, extracellular myoglobin (Mb), which accumulates in kidney, has been identified as a damaging pro-oxidant. We hypothesised that Mb mediated oxidative stress is the mechanism underpinning myoglobinuric AKI and consequently, antioxidant supplementation prior to insult may improve renal damage. Aim: Investigate the effects of antioxidants Bisphenol (BP), vit E and Selenium (Se) in cell and animal models of myoglobinuria. A major part of the studies undertaken in cell and animal studies were published and are described in chapters 2, 3 and 4. Methods: We investigated the effects of BP and Se on canine epithelial cells (MDCKII), rat model of myoglobinuria and also human carotid endothelial cells (HCECs). Tissue uptake of BP and vit E was measured using reverse phased HPLC and Se was measured using X-ray fluorescence. Markers for oxidative stress, inflammation and vascular resistance were assessed using various methods. Results: Our studies demonstrated that BP ameliorates Mb mediated oxidative stress in epithelial cells, putatively suggesting that strengthening the total antioxidant capacity of kidney may protect against oxidative stress induced by experimental myoglobinuria and prevent AKI following RM. However, in the rat model of myoglobinuria, it was conclusively proved that supplementation with BP and vit E although ameliorates oxidative stress and restores aortic vascular function, it was not adequate to prevent AKI following experimental rhabdomyolysis. Since both BP and vit E are likely to associate with the lipid compartment within renal tissues, we also tested the efficacy of a water-soluble compound Selenite in protecting renal tissues from damage post RM. This study proved that the Se, irrespective of its solubility, was not adequate to restore renal function under these experimental conditions and vascular dysfunction plays a more significant role promoting renal dysfunction than oxidative stress. To explain the failure of Se to ameliorate renal function, we investigated the effect of Mb induced oxidative stress on endothelial cells exclusively, to understand its role in progression of AKI. The experimental data suggested that endothelial cells exposed to extracellular Mb showed characteristics typical of increased vascular resistance. Conclusion: The outcomes of our research have significantly contributed to a better understanding of the mechanistic basis of AKI following rhabdomyolysis. Our data helps clarify the growing conflict in the literature that causally links Mb-derived oxidative stress and AKI and proposes vascular dysfunction mediated by reduced •NO and increased Ang II sensitivity as a major contributor of increased renal vascular tone, which in turn may compromise renal microcirculation, leading to reduced renal perfusion and precipitation of cast material. Further research is required to identify suitable therapeutics to reverse this pathology.