Effects Of HMG-CoA Reductase Inhibitor On Proliferation And Extracellular Matrix Secretion In Cyst-Lining Epithelial Cells And Fibroblasts Of Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic hereditary renal disease that ultimately results in renal insufficiency in more than one half of affected individuals.Nowadays there is no effective treatment to protect against progression of ADPKD.Although the cellular and molecular aspects of cystogenetic mechanisms are still not quit clear,it has been found that the proliferation of cyst-lining epithelial cells and fibroblasts,and remodeling of the extracellular matrix (ECM) play a critical role in cyst formation and interstitial fibrosis of ADPKD. HMG-CoA reductase inhibitors (HCRI) are a new class of lipid-lowering agents that have been extensively used clinically now.These agents not only are able to improve hyperlipidemia,but also directly inhibit cell proliferation and inflammation,induce apoptosis,prevent ECM deposition and renalinterstitial fibrosis. In vitro experiments have shown that HCRI is able to inhibit proliferation of cultured mesangial cells,renal epithelial tubular cells,and interstitial fibroblasts .It has been reported that treatment with HCRI ameliorates glomerular injury and tubulointerstitial fibrosis in several experimental models of progressive glomerular disease.Importantly,in the Han:SPRD rat model of hereditary polycystic kidney disease ,lovastatin-treated heterozygous males have milder disease with smaller cysts and lower plasma urea as compared with untreated animals.The present investigation is performed to elucidate the role of lovastatin ,an inhibitor of HMG-CoA reductase,in proliferation,ECM secretion and a l ( I ) collagen promoter activity in cultured ADPKD cyst-lining epithelial cells and fibroblast.Part I Effect of HCRI on proliferation of ADPKD cyst-lining epithelial cells and fibroblastsObjective To investigate the effect of lovastatin on proliferation of ADPKD cyst-lining epithelial cells and fibroblasts. Methods Cultured ADPKD cyst-lining epithelial cells and fibroblasts were incubated in RPMI1640 containing 2% fetal calf serum in the absence or presence of different concentration lovastatin and geranylgeranyl pyrophosphate (GGPP) for 24 or 48 hours.Cellproliferation was assessed by the MTT colorimetric assay. Results After ADPKD cyst-lining epithelial cells and fibroblasts were exposed 1 to 50 u mol/L lovastatin for 24 or 48 hours,their proliferation were significantly inhibited.The effects increased with the concentration of lovastatin,which suggested that lovastatin could inhibit the proliferation of ADPKD cyst-lining epithelial cells and fibroblasts in a dose-dependent manner.GGPP was able to reverse the growth inhibition of lovastatin in ADPKD cyst-lining epithelial cells and fibroblasts. Conclusion The present results suggest that GGPP plays a important role in proliferation of ADPKD cyst-lining epithelial cells and fibroblasts.lovastatin can inhibit these cells proliferation,which may be related to its inhibitory effect on GGPP production.Part II Effect of HCRI on extracellular matrix secretion of ADPKD cyst-lining epithelial cells and fibroblastsObjective ECM accumulation has been regarded as one of ADPKD pathological features.The ECM in cyst basement membrane and interstitium comes from ADPKD cyst-lining epithelial cells and fibroblasts separately.In this study we investigate the effect of lovastatin on ECM secretion of ADPKD cyst-lining epithelial cells and fibroblasts. Methods Cultured ADPKD cyst-lining epithelial cells and fibroblastswere incubated in RPMI1640 containing 2% fetal calf serum in the absence or presence of different concentration lovastatin and GGPP for 48 hours.Type I collagen,type III procollagen and type IV collagen were determined by radioimmunoassay.Results After ADPKD cyst-lining epithelial cells and fibroblasts were exposed 1 to 50 u mol/L lovastatin for 48 hours,type I collagen and type IV collagen secretion were significantly inhibited in a dose-dependent manner,except 1 u mol/L lovastatin for type I collagen secretion of cyst-lining epithelial cells,but it had no effect on type...