Heme oxygenase-1 induction by the ROS–JNK pathway plays a role in aluminum-induced anemia

• Aluminum (Al) overload induces HO activity and leads to hypochromic anemia in rats.
• The increase of HO activity is due to induction of HO-1.
• Al exposure increases the production of ROS in rat hepatocytes.
• The ROS–JNK signal pathway regulates HO-1 expression in Al-treated cells.

Aluminum (Al) overload is correlated with hypochromic anemia. It is possible that Al impedes heme biosynthesis and degradation by affecting the activity of biosynthetic enzymes. However, the molecular mechanisms by which Al affects these enzymes are unknown. Here, we show that long-term exposure of Sprague–Dawley rats to Al decreased hemoglobin concentration and the hematocrit level. In addition, the activity of aminolevulinic acid dehydratase (ALA-D) in rat liver was reduced, but heme oxygenase (HO) activity was enhanced, suggesting an impairment of heme homeostasis. The increase in HO activity was due to up-regulation of mRNA and protein of an inducible HO isozyme, HO-1. Furthermore, we found that reactive oxygen species (ROS)-mediated activation of c-Jun N-terminal kinase (JNK) was critical for HO-1 induction by Al, because ROS scavengers and JNK inhibitors abrogated enhancement of HO-1 by Al in rat hepatocytes. Thus, Al enhances HO-1 expression through the ROS–JNK pathway, which may enhance HO activity and accelerate degradation of heme, leading to hypochromic anemia.

Long-term exposure of aluminum induces the production of reactive oxygen species (ROS) and activates the c-Jun N-terminal kinase (JNK) pathway, which subsequently up-regulates the expression of HO-1 in rat hepatocytes. The increase in HO-1 protein enhances HO activity and accelerates heme degradation, which is correlated with hypochromic anemia.Figure optionsDownload as PowerPoint slide