Lovastatin-induced inhibition of renal epithelial tubular cell proliferation involves a p21ras activated, AP-1-dependent pathway.
Proliferation of tubular epithelial cells underlies the development of cystic lesions and the subsequent impairment of renal function after renal mass reduction. The effect of HMG CoA reductase inhibitors (HRI) on cell proliferation was investigated in rat renal proximal tubular epithelial cells in primary culture. Treatment of renal tubular epithelial cells with three different HRI reduced fetal calf serum (FCS)-induced [3H]-thymidine incorporation (IC50 values were 0.7 microM, 1.7 microM, and 1.6 microM for simvastatin, lovastatin, and compactin, respectively), and lovastatin blocked BrdUrd incorporation, as assessed by immunocytochemical studies. The proliferative effect of epidermal growth factor (EGF) was similarly abolished by lovastatin. The effect of lovastatin (1 microM) was prevented by 100 microM mevalonate, 5 microM farnesyl-pyrophosphate and 5 microM geranylgeranyl-pyrophosphate (in percent of control value, 31% vs. 102%, 60%, and 82%, respectively) while cholesterol and other products of the mevalonate pathway were inactive. Immunoblot analysis showed that lovastatin decreased membrane-bound p21ras and inhibited FCS-induced c-fos and c-jun protein expression. Furthermore, electrophoretic mobility shift assay demonstrated the functional impairement of AP-1 DNA binding activity in lovastatin-treated cells. In conclusion, these results demonstrate that HRI are antiproliferative in epithelial tubule cells and that this effect is exerted, at least in part, via inhibition of the p21ras-activated and AP-1 dependent mitogenic cascade.
Vrtovsnik
F
F
Department of Physiology, Faculté de Médecine Xavier-Bichat, Université Denis-Diderot, Paris, France.
Couette
S
S
Prié
D
D
Lallemand
D
D
Friedlander
G
G
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D006133:Growth Substances / Q000502:physiology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007668:Kidney / Q000166:cytology* / Q000502:physiology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects; D008148:Lovastatin / Q000494:pharmacology*; D015689:Oncogene Protein p21(ras) / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology; D017978:Receptors, Growth Factor / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000502:physiology
D006133:Growth Substances; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017978:Receptors, Growth Factor; D018808:Transcription Factor AP-1; D008148:Lovastatin; D020794:Receptor Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D015689:Oncogene Protein p21(ras)