Bessho Kazuhiko, Mizuno Shinya, Matsumoto Kunio, Nakamura Toshikazu
Division of Molecular Regenerative Medicine, Course of Advanced Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
Am J Physiol Renal Physiol. 2003 Jun;284(6):F1171-80. doi: 10.1152/ajprenal.00326.2002. Epub 2003 Feb 20.
Activation and proliferation of glomerular mesangial cells play an important role in the development of mesangioproliferative glomerulonephritis. We investigated the role of hepatocyte growth factor (HGF) in regulating activated mesangial cell proliferation. In glomeruli of normal rats, mesangial cells barely expressed the c-Met/HGF receptor. However, when mesangioproliferative glomerulonephritis was induced in rats by the administration of an anti-Thy 1.1 antibody, glomerular HGF expression transiently decreased along with mesangiolysis, and activation of mesangial cells was associated with upregulation of the c-Met receptor. Activated mesangial cells in culture also expressed the c-Met/HGF receptor. Although addition of HGF to cultured mesangial cells did not increase DNA synthesis, HGF did diminish PDGF-induced DNA synthesis. PDGF induced activation of ERK, which continued for at least 48 h. When PDGF and HGF were simultaneously added, HGF inhibited the prolonged activation of ERK, which suggests that early inactivation of PDGF-induced ERK may be involved in the inhibitory effect of HGF on mesangial cell proliferation. Furthermore, administration of HGF to rats with anti-Thy 1.1 nephritis resulted in a selective suppression of activated mesangial cell proliferation, and this suppressive effect was associated with attenuation of phosphorylated glomerular ERK. These results indicate that HGF counteracts PDGF-induced mesangial cell proliferation and functions as a negative regulator of activated mesangial cell proliferation.
肾小球系膜细胞的激活和增殖在系膜增生性肾小球肾炎的发展中起重要作用。我们研究了肝细胞生长因子（HGF）在调节活化系膜细胞增殖中的作用。在正常大鼠的肾小球中，系膜细胞几乎不表达c-Met/HGF受体。然而，当通过给予抗Thy 1.1抗体诱导大鼠发生系膜增生性肾小球肾炎时，肾小球HGF表达随系膜溶解而短暂下降，系膜细胞的激活与c-Met受体的上调相关。培养的活化系膜细胞也表达c-Met/HGF受体。虽然向培养的系膜细胞中添加HGF不会增加DNA合成，但HGF确实会减少血小板衍生生长因子（PDGF）诱导的DNA合成。PDGF诱导细胞外信号调节激酶（ERK）的激活，这种激活持续至少48小时。当同时添加PDGF和HGF时，HGF抑制ERK的持续激活，这表明PDGF诱导的ERK的早期失活可能参与了HGF对系膜细胞增殖的抑制作用。此外，向患有抗Thy 1.1肾炎的大鼠施用HGF导致活化系膜细胞增殖的选择性抑制，并且这种抑制作用与磷酸化肾小球ERK的减弱相关。这些结果表明，HGF可对抗PDGF诱导的系膜细胞增殖，并作为活化系膜细胞增殖的负调节因子发挥作用。
