Antiproliferation And Apoptosis Induction Effects Of HMG CoA Reductase Inhibitor On ADPKD Cyst-lining Epithelial Cell Line

Objective:Dysregulsted proliferation /apoptosis plays an important role in cyst formation in patient with Autosomal Dominant Polycystic Kidney Disease(ADPKD). A number of proto-oncogene have been shown overexpression in human and animal polycystic kidney disease, such as Ha-ras.. Ka-ras. c-fos. c-jun. c-myc. These proto-oncogenes, related to proliferation and apoptosis, probably cause cyst formation in ADPKD. Studies have shown that inactive p2lras can inhibit proliferation and induce apoptosis in many kinds of cells. Studies in Han:SPRD rat have demonstrated that HMG CoA reductase inhibitors (l-IRl) can retard the progress of cyst. We investigate the effect If HRI that inhibit proliferation and induce apoptosis on ADPKD cyst-lining epithelial cell and its possible mechanism.Methods:ADPKD cyst-lining epithelial cell were exposed to different concentration HRI (lovastatin simvastatin pravatastin) and geranylgeranyl prophosphate(GGPP).. farnesyl prophosphate(FPP) for 24 or 48 hours. Cell viability was assayed by the methods of MIT. Acridine orange technique and electron microscope were used to detect the morphological changes of ADPKD cyst-lining epithelial cell after exposed to lovastatin for 24 hours. DNA integrity and cell cycle were assessed by flow cytometry. Western blotting was used to detect p2lras located in cell membrane. The expression of c-jun and c-fos in ADPKD cyst-lining epithelial cell was assessed by immunocytochemistiy.Results: After ADPKD cyst-lining epithelial cell were exposed to HRI for 24 or 48 hours, proliferation was markedly inhibited, except pravastatin for24hours. The effects increased with the concentration of HRI, which suggested that HRI inhibited proliferation of ADPKD cyst-lining epithelial cell in a concentration dependent manner. GGPP or FPP reversed the grcmth inhibition of HRI in ADPKD cyst-lining epithelial cell. This implied that theantiproliferation of HRI was involved a non-sterol decrease. After ADPKD cyst-lining epithelial cell exposed to lovastatin for 24 hours, acridine orange technique and electron microscope showed the increasing apoptosis of ADPKD cyst-I ining epithel ial cell (P