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Blood, 1 September 2000, Vol. 96, No. 5, pp. 1716-1722
HEMATOPOIESIS
NG-monomethyl-L-arginine inhibits
erythropoietin gene expression by stimulating GATA-2
Takahisa Tarumoto,
Shigehiko Imagawa,
Ken Ohmine,
Tadashi Nagai,
Masato Higuchi,
Nobuo Imai,
Norio Suzuki,
Masayuki Yamamoto, and
Keiya Ozawa
From the Department of Hematology, Jichi Medical
School, Minamikawachi-machi, Tochigi-ken, Japan; Division of
Hematology, Institute of Clinical Medicine, University of Tsukuba,
Tennoudai, Tsukuba, Ibaraki, Japan; Center for Tsukuba Advanced
Research Alliance and Institute of Basic Medical Sciences, University
of Tsukuba, Tennoudai, Tsukuba, Ibaraki, Japan; Chugai Pharmaceutical
Co, Ltd, Tokyo, Japan.
NG-monomethyl-L-arginine (L-NMMA) has been
reported to be elevated in uremic patients. Based on the hypothesis
that the pathogenesis of the anemia of renal disease might be due to
the perturbation of transcription factors of the erythropoietin
(Epo) gene by L-NMMA, the present study was designed to
investigate the effect of L-NMMA on Epo gene expression
through the GATA transcription factor. L-NMMA caused decreased levels
of NO, cyclic guanosine monophosphate (cGMP), and Epo protein in Hep3B
cells. L-NAME (analogue of L-NMMA) also inhibited Epo production in
anemic mice. Transfection of the Epo promoter-luciferase gene into
Hep3B cells revealed that L-NMMA inhibited the Epo promoter activity.
However, L-NMMA did not inhibit the Epo promoter activity when mutated
Epo promoter (GATA to TATA) was transfected, and L-NMMA did not affect
the enhancer activity. Electrophoretic mobility shift assays
demonstrated the stimulation of GATA binding activity by L-NMMA.
However, L-NMMA had no effect on the binding activity of hepatic
nuclear factor-4, COUP-TF1, hypoxia-inducing factor-1, or NF- B.
Furthermore, cGMP inhibited the L-NMMA-induced GATA binding activity.
L-NMMA also increased GATA-2 messenger RNA expression. These results
demonstrate that L-NMMA suppresses Epo gene expression by
up-regulation of the GATA transcription factor and support the
hypothesis that L-NMMA is one of the candidate substances that underlie
the pathogenesis of renal anemia.
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