Renal proximal tubular cell growth and differentiation are differentially modulated by renotropic growth factors and tyrosine kinase inhibitors.
BACKGROUND
The renotropic growth factors (GFs), hepatocyte GF (HGF), epidermal GF (EGF), and insulin-like GF-I (IGF-I) accelerate renal regeneration in animal models after toxic or ischemic injury. These GFs initiate their biological effects on renal tubular cells by interaction with specific transmembrane receptor tyrosine kinases.


METHODS
In the proximal tubular cell line PT-1, the biological effects of HGF, EGF, and IGF-I and the growth-inhibitory effects of different tyrosine kinase inhibitors (TKIs) were investigated. Receptor binding and tyrosine kinase phosphorylation were determined by ligand binding studies and Western blot analysis.


RESULTS
HGF, EGF, and IGF-I bound with nanomolar affinity to their specific cell membrane receptor tyrosine kinases. In contrast to EGF or IGF-I, HGF induced a variety of cell morphological changes, including cell scattering, formation of tubular structures, and expression of long microvilli on the apical cell membrane. HGF was a 10-fold more potent and more effective growth promoter than EGF or IGF-I. Among the TKIs tested, the mitogenic effect of HGF could be more specifically inhibited by emodin and tyrphostin, that of EGF by methyl-2,5-dihydroxycinnamate, lavendustin A, and genistein, and that of IGF-I by geldanamycin.


CONCLUSIONS
In contrast to EGF and IGF-I, HGF stimulated both growth and differentiation of renal proximal tubular cells, demonstrating the amazing biological potency of this renotropic growth factor. Selective TKIs may be a promising approach to modulate diseases with abnormalities in protein kinase signalling pathways such as renal cell carcinoma.
Ernst
F
F
Division of Nephrology, Department of Internal Medicine II, University of Ulm, Robert-Koch-Strasse 8, D-89081 Ulm, Germany.
Hetzel
S
S
Stracke
S
S
Czock
D
D
Vargas
G
G
Lutz
M P
MP
Keller
F
F
Jehle
P M
PM
D000818:Animals; D001667:Binding, Competitive; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D006133:Growth Substances / Q000378:metabolism / Q000494:pharmacology*; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D007457:Iodine Radioisotopes; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011817:Rabbits; D017978:Receptors, Growth Factor / Q000378:metabolism
D004791:Enzyme Inhibitors; D006133:Growth Substances; D007457:Iodine Radioisotopes; D017978:Receptors, Growth Factor; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I; D011505:Protein-Tyrosine Kinases