Abstract
Abstract SCI-26
The kidney is often the target of injury by heme proteins and states of iron overload. Exogenous heme proteins, such as hemoglobin delivered to the kidney in hemolytic states, or myoglobin imposed upon the kidney following rhabdomyolysis, can injure the kidney via pathways that include vasoconstriction, direct cytotoxicity, and tubular cast formation. The former two pathways critically involve the heme prosthetic group: heme can bind vasodilator gases such as nitric oxide and carbon monoxide, while free heme can be cytotoxic because it is lipophilic, lipid membrane-transmissible, lipid membrane-destabilizing, prooxidant, and proinflammatory. Renal injury can also arise from endogenous heme proteins, such as cytochrome P450 enzymes, which can be destabilized by ischemic and nephrotoxic insults; such destabilization leads to the release of heme and incurs heme-dependent injury. The toxicity of heme may also reflect, at least in part, the release of iron and the attendant increase in labile cellular iron, the latter representing a potent catalyst for oxidative stress; increased levels of cellular iron may also originate from intracellular nonheme sources. Heme-iron can not only induce acute kidney injury, but also can provoke chronic kidney disease by virtue of its proinflammatory and profibrotic effects. Mechanisms that protect against heme-dependent and iron-dependent toxicity include heme oxygenase (HO), the rate-limiting enzyme in heme degradation, and increased synthesis of ferritin. Induction of HO-1, the inducible HO isoform, is protective against renal injury because of the following mechanisms: 1) the prevention of acute elevation in cellular heme concentrations otherwise incurred by cell injury; 2) the safe sequestration of iron in iron-binding proteins such as ferritin, or the cellular extrusion of iron by iron-exporting proteins; 3) the generation of antioxidant, anti-inflammatory metabolites such as bile pigments; and 4) the generation of carbon monoxide which is an antiapoptotic, anti-inflammatory, and vasorelaxant gas. Carbon monoxide can also be cytoprotective by binding cytochrome P450 enzymes, and thereby preventing their destabilization and the release of heme that subsequently occurs. In addition to these areas, this presentation discusses the pathobiologic and clinical significance of the siderophore-binding protein, NGAL (Neutrophil gelatinase-associated lipocalin): NGAL protects against renal ischemic injury through mechanisms that require the induction of HO-1; NGAL is increasingly utilized as a biomarker of acute kidney injury. The presentation concludes by discussing the use of iron supplementation in the treatment of anemia of chronic kidney disease and therapeutic strategies that may be designed from understanding endogenous and adaptive mechanisms that protect against the toxicity of heme-iron.
Disclosures:
No relevant conflicts of interest to declare.
Inhibition of cytochrome P450 2E1 and activation of transcription factor Nrf2 are renoprotective in myoglobinuric acute kidney injury
