Nephrology Dialysis Transplantation, Vol 13, Issue 6 1398-1405, Copyright © 1998 by Oxford University Press
S Stracke, F Ernst, D Jehle, R Grunewald, H Haller, F Keller and P Jehle
Background: As a renotropic cytokine, hepatocyte
growth factor (HGF) prevents acute renal failure and accelerates renal
regeneration. HGF initiates its biological effects by interaction with
specific transmembrane receptors, the c-Met proto-oncogene, possessing an
intracellular tyrosine kinase domain. We tested the hypothesis of whether
the complex biological effects of HGF in renal proximal tubular cells are
mediated by different intracellular signalling cascades and/or different
receptors. Methods: PT-1 cells, a proximal tubular
cell line derived from rabbit kidney, were cultured under defined
serum-free conditions to examine the biological effects of exogenously
added HGF. By specific assays, we determined HGF binding and its effects on
cell proliferation, migration, scattering and tubulogenic differentiation.
To investigate whether HGF action could be inhibited by protein tyrosine
kinase inhibitors (PTKIs), cells were incubated with HGF and different
concentrations of herbimycin A, genestein, methyl-2,5-dihydroxycinnamate
(MDC) and geldanamycin. All PTKIs are known inhibitors of
pp60c-src, a non-receptor tyrosine kinase involved
in cell growth control. Results: HGF bound with high
affinity to cell membrane receptors and displayed multiple biological
effects. Compared with serum-free controls, HGF increased the number of
microvilli 1.5-fold, enhanced cell proliferation and migration 1.8-fold,
and stimulated the formation of tubular structures 2.3-fold. Consistent
with the known tyrosine kinase activity of the c-Met receptor, the
mitogenic and motogenic effects of HGF were inhibited by PTKIs in a
dose-dependent manner with the following order of potency:
geldanamycin>herbimycin A>genestein>MDC. In contrast,
however, the HGF-induced tubulogenic cell differentiation was not inhibited
specifically by PTKIs. Conclusions: The finding that
PTKIs inhibited the mitogenic response but not the tubulogenic
differentiation induced by HGF indicated different intracellular signal
transduction pathways. We suggest that pp60c-src
plays a key role in mediating the mitogenic and motogenic action of HGF,
whereas tubulogenic cell differentiation induced by HGF is transduced by a
pp60c-srcindependent signalling pathway.
Key words: HGF; p60c-src,
protein tyrosine kinase inhibitors; renal proximal tubular cells; signal
transduction
ORIGINAL ARTICLES
Differentiating and proliferative effects of HGF in renal proximal tubular cells are mediated via different signalling pathways
Department of Internal Medicine II, Division of Nephrology, University of Ulm, Robert-Koch-Str 8, D-89081 Ulm, Germany; Department of Nephrology, University of Gottingen, Germany; Department of Nephrology, Franz-Volhard-Klinik, Humboldt University of Berlin, Germany; Corresponding author
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