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Lovastatin-induced inhibition of renal epithelial tubular cell proliferation involves a p21ras activated,
F Vrtovsnik1, S Couette, D Prié
1Department of Physiology, Faculté de Médecine Xavier-Bichat, Université Denis-Diderot, Paris, France.
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 (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.
Insights
HMG CoA reductase inhibitors (HRI) reduce renal tubular epithelial cell proliferation, a key factor in kidney cyst development. These statins inhibit crucial cell signaling pathways, offering potential therapeutic benefits for kidney disease.
Area of Science:
- Nephrology
- Cell Biology
- Pharmacology
Background:
- Tubular epithelial cell proliferation is a key factor in cystic kidney disease development following renal mass reduction.
- Understanding the mechanisms that regulate this proliferation is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the effects of HMG CoA reductase inhibitors (HRI) on the proliferation of rat renal proximal tubular epithelial cells.
- To elucidate the specific molecular pathways targeted by HRI in inhibiting cell growth.
Main Methods:
- Primary culture of rat renal proximal tubular epithelial cells.
- Assays for [3H]-thymidine and BrdUrd incorporation to measure cell proliferation.
- Western blot analysis for p21ras, c-fos, and c-jun protein expression.
- Electrophoretic mobility shift assay (EMSA) to assess AP-1 DNA binding activity.
Main Results:
- Three different HRI (simvastatin, lovastatin, compactin) significantly reduced fetal calf serum (FCS)-induced [3H]-thymidine incorporation.
- Lovastatin inhibited both BrdUrd incorporation and the proliferative effects of epidermal growth factor (EGF).
- Lovastatin's effects were reversed by mevalonate, farnesyl-pyrophosphate, and geranylgeranyl-pyrophosphate, but not by cholesterol.
- Lovastatin decreased membrane-bound p21ras, inhibited FCS-induced c-fos and c-jun expression, and impaired AP-1 DNA binding activity.
Conclusions:
- HMG CoA reductase inhibitors exhibit antiproliferative effects on renal epithelial tubule cells.
- These effects are mediated, at least in part, by the inhibition of the p21ras-activated and AP-1 dependent mitogenic signaling cascade.
- HRI represent a potential therapeutic strategy for conditions characterized by excessive tubular epithelial cell proliferation, such as cystic kidney diseases.