| [ Summary ] |
It has been reported that NG-monomethyl-L-arginine (L-NMMA) was undetectable in non-uremic subjects, but markedly elevated in uremic subjects. Based on this observation, we hypothesized that L-NMMA is a candidate uremic toxin, responsible for the anemia related to renal disease. However, the function of L-NMMA in mediating EPO gene expression has not been elucidated. Since L-NMMA functions as an inhibitor of NOS, it was expected that it would suppress the production of NO and cGMP. GATA transcription factors have been demonstrated to bind to the GATA element in the EPO promoter and negatively regulate EPO gene expression. In our previous study, we found that L-NMMA decreased the expression of NO and cGMP and increased the expression of GATA-2 mRNA and levels of GATA-2 binding activity, thereby inhibiting EPO promoter activity and causing a decrease in the expression level of EPO proteins. In the present study, we examineted the possibility of the use of L-arginine as a supportive therapy for the anemia related to renal disease. The results of an in vivo mouse assay revealed that L-NAME (an analogue of L-NMMA) inhibited the expression of EPO, but this inhibition of EPO expression by L-NAME was rescued by pretreatment with L-arginine. These findings suggest that L-arginine could be used to treat anemia related to renal disease. |