Kidney-liver dialogue in acute kidney injury.

HEMOPEXIN IS A MULTIFUNCTIONAL serum glycoprotein that plays important roles in iron homeostasis, antioxidant protection, anti-inflammatory effects, and signal transduction pathways (6, 8). The liver is the main source of the hemopexin synthesis (7), but expression in other tissues including the retina, peripheral nerves, and neurons of the central nervous system has also been reported. Hemopexin is a positive acute-phase reactant protein that binds free heme with strong affinity (6). The amount of free heme in the plasma is considerably increased when it is liberated from heme-containing proteins due to hemolysis or rhabdomyolysis. Free heme is toxic to cells, and its toxicity is contributed by its divalent catalytic iron (redoxactive iron), which promotes oxidative stress, resulting in tissue and organ injury (4, 9). In addition, free heme is capable of intercalating in membranes and oxidizing lipids and proteins in the membranes. Hemopexin prevents heme toxicity by sequestering free heme from the bloodstream and transporting it to the liver. Specific receptors in the liver cells help in the receptor-mediated endocytosis of hemopexin-sequestered heme and subsequently hemopexin delivers heme into the liver cells for degradation (2). Following delivery of heme, hemopexin becomes available for further transport and recycling of free heme to the liver. The current paradigm is that injury to the kidney results in a cross talk that affects several distant organs including the liver, heart, and lungs (1). In keeping with this paradigm Zager et al. (1) demonstrate in an issue of the American Journal of PhysiologyRenal Physiology that, in response to experimental acute kidney injury (AKI) induced by glycerol, cisplatin, ischemiareperfusion, and lipopolysaccharide endotoxemia, there is an increase in liver hemopexin levels resulting from increased synthesis as reflected by an increase in messenger RNA levels. The interesting finding reported in this study relates to an increase in hemopexin levels in the kidney. Zager et al. argue that an increase in hemopexin levels in the kidney is not accounted for entirely by increased synthesis but rather by the uptake of hemopexin by the kidney. The evidence includes an increase in plasma hemopexin levels, which they suggest originate from the liver; a marked increase in hemopexin levels in the kidney without a significant increase in messenger RNA; luminal and cytoplasmic immunohistochemical localization of hemopexin with droplets of hemopexin in proximal tubular cells; and excretion of hemopexin in the urine. The findings on the staining pattern and urinary excretion of hemopexin were interpreted as uptake and endocytic reabsorption of hemopexin in the proximal tubule. The authors believe that this represents a new paradigm in that there is reverse cross talk (liver impacting the kidney by providing it hemopexin) and have termed the accumulation of hemopexin in the kidney as “renal hepatization.” This finding extends their recent observation related to other proteins synthesized in the liver including albumin, -fetoprotein, and haptoglobin that were expressed in the kidney during ischemic and toxic renal damage. The notion of reverse cross talk and renal hepatization are interesting concepts with potentially important pathophysiological implications. However, additional evidence that this indeed is the case would be important before the concept of reverse cross talk is fully accepted. As an example, in the context of this study, it would be important to show that tagged hemopexin infused in the plasma is taken up by the kidney. In addition, the underlying mechanism involved in uptake requires further study. For example, the mechanism of uptake of heme from hemopexin-sequestered heme by liver cells is well studied and involves receptor-mediated uptake of heme by the liver cells. The elucidation of the mechanism of uptake of hemopexin will provide further evidence of its uptake by proximal tubular epithelial cells in AKI. Another interesting finding that Zager et al. (10) have reported is that significant levels of plasma free heme are increased at the very early stages of induction of experimental AKI. Since free heme is prooxidant and toxic to cells, it may result in systemic injurious effect to the kidney and other organs (1, 4, 9). The elevated levels of plasma heme at the initiation phase of AKI were transient and considerably reduced to subnormal values at later stages in all models of AKI. The reduction in free heme levels was attributed to the upregulation of plasma hemopexin levels that can bind excess free heme. Severe renal damage has been shown previously in hemopexin-deficient mice (9), supporting the role of hemopexin as a protective mechanism. However, one has to consider that heme oxygenase-1 is involved in the breakdown of free heme (3, 5) and can also participate in its reduction. Heme oxygenase-1 has been shown to provide a cytoprotective role in renal injury (3, 5). Therefore, both hemopexin and heme oxygenase-1 that downregulate heme will have beneficial effects in AKI. Another remarkable finding of the study is that, in cultured renal epithelial cells, iron or heme did not upregulate hemopexin but deferoxamine, an iron chelator, had a marked effect on the upregulation of hemopexin gene expression. It is known that iron chelators provide a renoprotective role during cisplatin and other AKI models. This has been attributed to iron chelation, but it is conceivable that induction of hemopexin could contribute to the protective effect of an iron chelator. The studies presented by Zager et al. (10) provide evidence to suggest reverse cross talk and renal hepatization in AKI. Additional studies to provide more conclusive evidence of these concepts and their relevance to the pathophysiological mechanisms in AKI and potential therapeutic implications appear to be important areas for further study.