Despite new insights into the pathogenesis of acute renal failure (ARF), neither the incidence nor mortality from this disease has declined over 30 years. This may be due to the fact that most newly defined pharmacologic therapies must be administered during the induction phase of renal damage. Since ARF patients are typically seen only after the onset of renal damage, it may be too late to initiate renal protective therapy. One notable exception to this may be high risk patients undergoing surgery. Since this setting confers a high risk of ARF (>= 30% in some series), the intra-operative period could be an ideal time for initiating renal """"""""prophylactic"""""""" therapy . Our recent investigations (cell culture, isolated rat tubules, whole rats, surgical patients) indicate that currently used fluorinated anesthetics (e.e. isoflurane, sevoflurane, desflurane) and some of their degradative products (e.g. inorganic fluoride, fluorinated vinyl ethers) can markedly affect proximal tubule cell homeostasis. In high doses, overt nephrotoxicity results. Conversely, in low doses, some rapidly (<=3 hrs) trigger a potent cytoprotective state which is capable of mitigating superimposed ATP depletion/nephrotoxin- induced tubule necrosis and ARF. The proposed research seeks to ascertain determinants and mechanisms of this cytoprotective state in order to optimize its expression thereby potentially decreasing the risk of post-operative ARF. Towards these ends, three specific aims are proposed 1) Define the role of anesthetic metabolism as a determinant of anesthetic toxicity and cytoprotection. The available data suggests that cytochrome P450 and non P450 metabolism impact anesthetic effects on proximal tubule homeostasis. The basis for this will be explored to: a) define underlying mechanism for these actions; b) to ascertain ways to pharmacologically enhance the expression of anesthetic """"""""cytoprotective"""""""" vs. """"""""injurious"""""""" effects 2)Define the mechanistic link between anesthetic """"""""toxicity"""""""" and """"""""cytoresistance"""""""". A plethora of information indicates that sub lethal injury can initiate adaptive responses that culminate in a cytoresistant state. Thus, """"""""injury"""""""" and ~protection~ can be two points on a spectrum. The role of 3 specific anesthetic effects on tubule homeostasis (mitochondrial injury, NaK-ATPase inhibition, PLA2/activation-depletion) as """"""""triggers"""""""" for anesthetic cytoresistance will be tested; and 3: Define mechanisms by which fluorinated anesthetics mitigate a specific model of ARF. These studies will test how fluorinated anesthetics specifically interact with specific subcellular pathways of a clinically relevant form of injury (myohemoglobin toxicity,) thereby protecting against ARF. In particular, the hypothesis will be tested that fluoride-induced alterations in PLA2 expression, mitochondrial free radical generation and NaK-ATPase activity act in concert to abrogate critical induction pathways of myohemoglobinuric ARF.
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