L-arginine rescues decreased erythropoietin gene expression by stimulating GATA-2 with L-NMMA

Shigehiko Imagawa, Takahisa Tarumoto, Norio Suzuki, Harumi Y. Mukai, Yuichi Hasegawa, Masato Higuchi, Tomohiro Neichi, Keiya Ozawa, Masayuki Yamamoto, Toshiro Nagasawa

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

Background. NG-monomethyl-L-arginine (L-NMMA) decreases the expression of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) and increases the expression of GATA-2 mRNA and levels of GATA-2 binding activity, thereby inhibiting erythropoietin (Epo) promoter activity and causing a decrease in the expression of Epo protein. In the present study, we examined the effect of L-arginine on Epo gene expression in Hep3B cells and BDF1 mice. Methods. Hep3B cells were incubated with and without different concentrations of L-NMMA and/or L-arginine. Anemic mice were injected with phosphate-buffered saline (PBS) or L-NAME and L-arginine. Results. Incubation with L-NMMA under hypoxic conditions inhibited Epo expression, but this inhibition was recovered by the addition of L-arginine. Hypoxia induced the secretions of NO and cGMP, but the addition of L-NMMA inhibited these inductions, though these inhibitions of NO and cGMP by L-NMMA were recovered by the addition of L-arginine. Hep3B cells transfected with the Epo promoter/enhancer-luciferase gene had Epo promoter activity. This activity was inhibited by L-NMMA, but it could be recovered by the addition of L-arginine. L-NMMA induced the binding activity of GATA-2 under hypoxic conditions. This binding activity was inhibited by the addition of L-arginine. The addition of cGMP inhibited L-NMMA-induced GATA-2 binding activity in a dose-dependent manner. The results of an in vivo mouse assay revealed that L-NAME inhibited the expression of Epo, but this inhibition of Epo expression by L-NAME was rescued by pretreatment with L-arginine. Conclusion. L-arginine rescues decreased erythropoietin gene expression by stimulating GATA-2 with NG-monomethyl-L-arginine.

Original languageEnglish
Pages (from-to)396-404
Number of pages9
JournalKidney international
Volume61
Issue number2
DOIs
Publication statusPublished - 2002

Keywords

  • Anemia
  • Hypoxia
  • L-NAME
  • L-NMMA
  • Oxygen sensing
  • Signal transduction
  • Uremic toxin

ASJC Scopus subject areas

  • Nephrology

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