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- Title
Lovastatin-induced inhibition of renal epithelial tubular cell proliferation involves a p21<em><sup>ras</sup></em> activated, AP-1-dependent pathway.
- Authors
Vrtovsnik, François; Couette, Sylviane; Prié, Dominique; Lallemand, Dominique; Friedlander, Gerard
- Abstract
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 (lC50 values were 0.7 μM, 1.7 μM, and 1.6 μM 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 μM) was prevented by 100 μM mevalonate, 5 μM farnesyl-pyrophosphate and 5 μM 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 p21<em>ras</em> 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 p21<em>ras</em>-activated and AP-1 dependent mitogenic cascade.
- Subjects
EPITHELIAL cells; CELL proliferation; PEPTIDES; MITOGENS; COWS; GENES
- Publication
Kidney International, 1997, Vol 52, Issue 4, p1016
- ISSN
0085-2538
- Publication type
Article
- DOI
10.1038/ki.1997.423