title: Counteractive effects of HGF on PDGF-induced mesangial cell proliferation in a rat model of glomerulonephritis.
abstract: 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.
authors.affiliation: Division of Molecular Regenerative Medicine, Course of Advanced Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Bessho
authors.forename: Shinya
authors.initials: S
authors.lastname: Mizuno
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D000963:Antimetabolites; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D005920:Glomerular Mesangium / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D005921:Glomerulonephritis / Q000139:chemically induced / Q000473:pathology*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000963:Antimetabolites; D010982:Platelet-Derived Growth Factor; D017228:Hepatocyte Growth Factor; D004247:DNA; D020928:Mitogen-Activated Protein Kinases; D001973:Bromodeoxyuridine