The Study of the Involvement of Micrornas in Pressure-Induced Initial Renal Fibrosis

The study of the involvement of microRNAs in pressure-induced initial renal fibrosis Chronic kidney disease (CKD) is a common, progressive illness that is becoming a global public health problem. Tubulointerstitial fibrosis is recognized as a key determinant of progressive CKD due to the strong correlation between the degree of interstitial fibrosis and renal functional loss. The possible mechanisms which may drive tubulointerstitial fibrosis are important for the study of CKD. Numerous cytokines and growth factors appear to modulate progression of tubulointerstitial fibrosis, such as TGF-, PDGF, AngII, basic FGF, endothelin, various chemokines, peroxisome proliferator-activated receptor- and PAI-1. However, the initial mechanism of tubulointerstitial fibrosis is poorly understood. Increasing evidence shows micro-RNAs regulate diverse biological processes including cell proliferation, differentiation and apoptosis, and are even involved in the development of multiple diseases. Although the study about the connection between miRNAs and renal fibrosis is rare, a few miRNAs have been proven to affect the signal pathway of renal fibrosis. It is envisaged that investigating the roles of miRNAs in renal fibrosis could not only advance our understanding of the pathogenesis of CKD, but might also provide new therapeutic targets. The primary goal of this project was to investigate the roles of miRNAs in early renal fibrosis. Recent evidence suggests that the pressure force is an important mechanism contributing to the induction and progression of tubulointerstitial fibrogenesis in ureteric obstruction and diabetic nephropathy. Therefore, we will study the pressure-induced tubulointerstitial fibrosis in both culture renal tubular cells and a unilateral ureteric obstruction animal model. For studying pressure-induced fibrosis in cellular level, we established a novel pressure apparatus to apply pressure directly to rat renal tubular cells (NRK-52E). By using this culture system and micro-array analysis, the miRNAs involved in the initial mechanism of pressure-induced renal fibrosis will be identified. In this 3-year project, the pressure-influenced miRNAs and their target genes will be investigated in vivo and in vitro. The specific aims of this project are listed as below: 1. To investigate specific miRNAs involved in pressure-induced initial renal fibrosis. 2. To identify the target genes for the specific miRNAs and their role in pressure-induced renal fibrosis. 3. To evaluate the associated signal transduction of the target genes in the initial progress of renal fibrosis.