Lovastatin Effects Transdifferentiation Of Rat Renal Tubular Epithelial Cell Induced By TGF-β

BACKGROUND: Tubularinterstitial fibrosis is believed to be thecommon final pathway leading to end-stage renal failure. Recently, the myofibroblast has been found to play an important role in the progression of renal interstitial fibrosis. Myofibroblast can accelerate cell growth, collagen synthesis and the deposit of ectracellular matrix (ECM). The characteristic protein of myofibroblast is named α -smooth muscle actin ( α -SMA). Previous study had showed that TGF- β can induce tubular epithelial-myofibroblast transdifferrntiation (TEMT) , and the connective tissue growth factor (CTGF) acts as a downstream effector of TGF- β . HMG-CoA retractor inhibitor was demonstrated recently to be effective in retarding the progression of renal interstitial fibrosis. The object of our research is to observe the effects of Lovastatin on TGF- β triggered TEMT, the express of CTGF and the synthesis of collagen type Ⅲ in TEMT.METHODS: The cultured NRK52E cells were divided into control group,TGF- β -treated group, TGF- β and Lovastatin-control with different dose. The morphology of the cells was observed by light microscope (LM) andscanning electron microscope (SEM). Immunohistochemistry was used to assess the a -SMA and CTGF express. Quantity analysis of a -SMA and CTGF mRNA were done by flowcytometry and RT-PCR independently. The collagen type HI synthesis is measured by ELISA.RESULTS: After 5 days, the cultured NRK52E cells in the TGF- ￡ -treatedgroup became elongated, with many cells showing fibroblast-like in appearance under LM and SEM. The changes found in the TGF- 3 -treated group also included the increase in percentage of a -SMA+ cells and in content of a -SMA protein measured by flowcytometry and the CTGF mRNA by PT-PCR (PO.05). Furthermore, collagen III synthesis was increased significantly (P<0.05) in the TGF- & -treated group. Treatment with Lovastatin for 6 days caused significant reductions in the a -SMA+ cells and the content of a -SMA and CTGF mRNA in a dose-dependent fashion (P<0.05). Treatment with Lovatatin also minimized the increase of the collagen III content. In addition, a -SMA+ cells was significantly associated with CTGF mRNA expression of NRK52E cells (r =0.914, PO.01), and the expresssion of collagen type III (r =0.935, PO.01). CTGF mRNA expression was correlated with content of collagen type III (r =0.965, PO.01).CONCLUSIONS: The results suggest that TGF- 0 can induce TEMT and increased the level of collagen III. Lovastatin can significantly inhibit the transdifferentiation of renal tubular epithelial cells and collagen III synthesis induced by TGF- P .. Lovastatin may down regulate TEMT through a machanism of inhibiting the expression of CTGF. Thus, Lovastatin may potentially be therapeutic in the management of renal fibrosis.