Rhabdomyolysis occurs in diverse conditions and accounts for a relatively common and potentially treatable cause for acute renal failure. So exposed to excessive amounts of heme proteins discharged during rhabdomyolysis, the kidney exhibits prompt and prominent renal vasoconstriction, tubular necrosis and cast nephropathy. We have recently demonstrated that heme proteins, in addition to inflicting injury, also elicit an adaptive response in the kidney consisting of the induction of heme oxygenase coupled to ferritin synthesis. We propose that the nephrotoxicity of heme proteins accrues from injury to multiple cellular targets inflicted dominantly, by heme released from heme proteins, as the latter are oxidized by the kidney. The presence of large amounts of heme within the intracellular compartment, however, also induces heme oxygenase and stimulates ferritin synthesis, a response that affords the clearance of heme and the sequestration of iron, the latter released when heme is degraded. The present proposal analyzes the linkage between injury and adaptation in the kidney induced by heme proteins in vivo and in vitro. The application also seeks to define aspects of renal function, in particular renal oxidative metabolism, that render the kidney vulnerable to heme-mediated toxicity. Additionally we propose that heme proteins directly induce renal vasoconstriction by virtue of the long recognized avidity with which heme proteins bind nitric oxide. Finally, we explore the extent to which the induction of heme oxygenase and ferritin underlies the phenomenon of cross resistance to acute renal failure.
Our specific aims i nclude i) the factors regulating the expression of heme oxygenase and ferritin in vivo in experimental rhabdomyolysis, ii) the mechanisms influencing the induction of heme oxygenase and ferritin by heme proteins in the intact kidney in vivo, and the correlation of such induction with renal injury, iii) the determinants and cellular targets of heme protein toxicity to renal epithelial cells in vitro and the correlation of such injury with induction of heme oxygenase and ferritin, iv) the capacity of heme proteins to bind nitric oxide as a determinant of vasoconstriction and, v) the role of induction of heme oxygenase and ferritin as a mechanism underlying cross resistance to other forms of acute renal failure. This proposal utilizes maneuvers which independently afford protection in experimental rhabdomyolysis in vivo, and these include the prior administration of heme proteins and pyruvate. Such strategies may be relevant to the therapy and prevention of clinical rhabdomyolysis.
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