Abstract
Itai-itai disease, developing based on proximal renal tubular injury due to cadmium (Cd) toxicity, often showed severe anemia associated with low serum levels of erythropoietin (EPO), which is mainly produced from kidneys. We observed levels of blood EPO and renal EPO induction in rats exposed to Cd and investigated the relationship between them to clarify the kinetics of EPO in Cd toxicity. Wistar rats were injected s.c. with saline or Cd at 2 mg/kg per week for 3 or 8 months. Then they were put under hypobaric hypoxia (0.65 or 0.55 MPa) for 3 hours to enhance EPO induction or stayed in normoxia. After that, peripheral blood and kidneys were taken. Serum samples were obtained from the blood to measure EPO concentration. Total RNA and paraffin block samples were prepared from the kidneys to observe EPO mRNA expression by real time PCR and highly sensitive in situ hybridization as well as hematoxylin-eosin staining, respectively. The Cd-injected rats showed injured renal tubules and anemia. The serum EPO levels were elevated by hypoxia, and tended to be higher in the Cd-injected rats than the saline-injected, although they were insufficient to compensate anemia. The renal EPO mRNA expression was enhanced by hypoxia, but the enhancement levels were smaller in the Cd-injected rats than the saline-injected. These results indicate that there was a discrepancy between renal EPO induction and blood EPO levels in the Cd-injected rats, suggesting that Cd induces EPO production from other organs, such as liver, to compensate the decreased capacity to produce EPO in kidneys.
