| Research Abstract |
Erythropoietin (Epo) gene expression is negatively regulated by GATA, which binds to the GATA site in the Epo promoted and also positively regulated by hypoxia inducible factor-1(HIF 1), which binds to the hypoxia responsive element (HRE) in the Epo enhancer. We have the following results along with this evidence
1) N^G-monomethyl L-arginine (L-NMMA) has been increased in the patients with chronic renal failure. The addition of L-NMMA(NOS inhibitor) into the Hep3B cells, inhibits NO・cGMP production, increases GATA binding activity and mRNA expression, ad inhibits Epo promoter activity and induces the anemia with renal disease (Blood 96 : 1716-1722, 2000). However, pre-treatment with L-arginine reversed the anemia with renal disease in vitro Hep3B cells and in an in vivo mouse assay (Kidney Int 61 : 39604, 2002)
2) The addition of H_2O_2 inhibits Epo gene expression by increasing GATA binding activity and inducing degradation of HIF-1α(J Cell Physiol 186 : 260-267, 2001)
3) The addition of
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cadmium inhibits Epo gene expression by inhibiting the binding activity of HIF-1, not by GATA (Arch. Toxicol 77 : 267-273, 2003)
4) Mouse Epo gene expression is also negatively regulated by GATA, which bonds to the GATA site in the mouse Epo promoter like human Epo gene (Int J Hematol 74 : 376 381, 2002)
5) To better understand how human adapt to hypoxia, the levels of Hb, serum Epo and VEGF were measured in 106 patients with severe obstructive sleep apnea-hypopnea syndrome. The results indicated that temporal hypoxic stimulation increases Hb. Furthermore, a minor increase in Epo and a substantial increase in VEGF were found (Blood 98:1255-1257, 2001)
6) K-7174 (a GATA-specific inhibitor) improved Epo production that had been inhibited by IL-1β and TNF-α, which have been increased in the patients with anemia of chronic disease or L-treatment in Hep3B cells in vitro, and in an in vivo mouse assay (FASEB J 17 : 1742-1744, 2003)
Recently, we have analyzed Epo gene expression system by transgenic mice with BAC to identify the kidney inducible element (KIE). Peritubular capillary interstitial cells are the major Epo productive cells. KIE is located between 22〜8Kbp upstream from CAP site (In preparation) Less
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