Abstract
Free heme, a pro-oxidant released from myoglobin, is thought to contribute to the pathogenesis of rhabdomyolysis-associated acute kidney injury (RM-AKI), because renal overexpression of heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme catabolism, confers protection against RM-AKI. BTB and CNC homology 1 (Bach1) is a heme-responsive transcription factor that represses HO-1. Here, we examined the changes with time in the gene expression of Bach1, HO-1, and δ-aminolevulinate synthase (ALAS1, a heme biosynthetic enzyme) in the rat kidney using an RM-AKI model induced by the injection of 50% glycerol (10 mL/kg body weight) into bilateral limbs. We also examined the protein expression of Bach1 in the nucleus and cytosol, and HO-1 in the rat kidney. Glycerol treatment induced significant elevation of serum creatinine kinase and aspartate aminotransferase levels followed by the marked elevation of serum blood urea nitrogen and creatinine levels, which caused serious damage to renal tubules. Following glycerol treatment, HO-1 mRNA and protein levels were significantly up-regulated, while ALAS1 mRNA expression was down-regulated, suggesting an increase in the free renal heme concentration. The Bach1 mRNA level was drastically increased 3 h after glycerol treatment, and the increased level was maintained for 12 h. Nuclear Bach1 protein levels were significantly decreased 3 h after treatment. Conversely, cytosolic Bach1 protein levels abruptly increased after 6 h. In conclusion, we demonstrate the dynamic changes in Bach1 expression in a rat model of RM-AKI. Our findings suggest that the increase in Bach1 mRNA and cytosolic Bach1 protein expression may reflect de novo Bach1 protein synthesis to compensate for the depletion of nuclear Bach1 protein caused by the induction of HO-1 by free heme.
Highlights
Rhabdomyolysis is associated with extensive muscle injury that is accompanied by the release of myoglobin, which causes severe oxidative damage, leading to acute kidney injury
We detected a significant increase in Heme oxygenase-1 (HO-1) expression and the robust inhibition of ALAS1 expression in the kidneys of glycerol-treated animals, suggesting a significant increase in the free heme concentration in the kidney of glycerol-treated animals
BTB and CNC homology 1 (Bach1) is a hemeresponsive transcription repressor of the HO-1 gene, and our findings suggest that changes in the subcellular distribution of Bach1 may be involved in the induction of HO-1 accompanying heme metabolism in the kidney of the rat rhabdomyolysisassociated acute kidney injury (RM-AKI) model
Summary
Rhabdomyolysis is associated with extensive muscle injury that is accompanied by the release of myoglobin, which causes severe oxidative damage, leading to acute kidney injury. Bach expression in acute kidney injury heme group from ferrous to ferric and to ferryl oxidation states to cause renal injury [1]. HO-1 protects against renal oxidative damage, suggesting that in addition to the heme moiety of myoglobin, free heme released from myoglobin contributes to the pathogenesis of RM-AKI [2, 3]. BTB and CNC homology 1 (Bach1) is a heme-responsive transcription factor that represses HO-1. In the presence of excess free heme, Bach1-Maf is released from MARE, allowing transcriptional activation of Ho-1 by nuclear factor (erythroid-derived 2)-like 2 (Nrf2)–Maf heterodimers [4,5,6,7]
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