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Inhibition of geranylgeranylation suppresses the proliferation of rat cultured mesangial cells
Author(s) -
HE JinSong,
HORIKOSHI Satoshi,
FUNABIKI Kazuhiko,
MAEDA Atsuko,
KOBAYASHI Michimasa,
SHIRATO Isao,
TOMINO Yasuhiko
Publication year - 2002
Publication title -
nephrology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 61
eISSN - 1440-1797
pISSN - 1320-5358
DOI - 10.1046/j.1440-1797.2002.00123.x
Subject(s) - geranylgeranylation , mesangial cell , cell growth , platelet derived growth factor receptor , microbiology and biotechnology , biology , kinase , growth factor , cancer research , prenylation , endocrinology , biochemistry , receptor , kidney , enzyme
SUMMARY: Mesangial hypercellularity is a critical early histopathological finding observed in human and experimental glomerular diseases. the regulation of mesangial cell proliferation may be crucial in the treatment of glomerular injury. Ras proteins are guanosine triphosphatases that regulate proliferation and differentiation by transducing biological information from extracellular signals to the nucleus. the blocking of Ras function by inhibitors of prenyltransferase has been shown to suppress the proliferation in several kinds of cell types. the objective of the present study was to examine the effects of selective inhibitors of farnesylation (FTI‐277) and geranylgeranylation (GGTI‐286) on proliferation of cultured rat mesangial cells. the incubation of mesangial cells with FTI‐277 and GGTI‐286 with stimulation by either 10% fetal calf cell (FCS) or platelet‐derived growth factor (PDGF) was performed, and bromo‐deoxyuridine (BrdU) incorporation was measured. Ras processing and mitogen‐active protein (MAP) kinase activation, after the incubation with 10% FCS, were also examined. Geranylgeranylation caused a dose‐dependent reduction of FCS or PDGF‐stimulated BrdU incorporation. Geranylgeranylation also inhibited the activation of MAP kinase, but not Ras processing, stimulated by 10% FCS. However, FTI‐277 had little effect on DNA synthesis and MAP kinase activation induced by FCS or PDGF, despite the inhibition of Ras processing. the present study showed that GGTI‐286 inhibited the proliferation of rat cultured mesangial cells. It appears that the antiproliferative effect of the geranylgeranyl transferase I inhibitor may be useful in preventing mesangial cell proliferation.