The role and molecular mechanism of PPARα in acute kidney injury: focus on the protective effect in renal tubular cell

The role and molecular mechanism of PPARα in acute kidney injury: focus on the protective effect in renal tubular cell Peroxisome proliferator-activated receptor-alpha (PPARα) is a transcription factor and has been reported to express protective effect on certain cell types. In previous study, we found that the activation of PPARαis important for the anti-apoptotic effect of prostacyclin (PGI2) in renal tubular cells. On the other hand, we also found that PPARαis capable of protecting renal tubular cells from adriamycin- and gentamicin-induced apoptosis. These data imply the therapeutic potential of PPARα for renal tubule damage. However, the detailed protective mechanism of PPARαis still unknown. In our preliminary data, we found that the expression of phospholipase C (PLC) and phosphor-Akt were induced in PPARαoverexpression cells revealed by 2D-gel and Western blotting. This result is still a novel finding in the study of the protective mechanism of PPARα. The PLC and PI3K-Akt signaling pathways play important roles in eukaryotic cell physiology, in particular signal transduction pathways. These pathways may be involved in the protective effect of PPARαin renal tubular cells. Additionally, 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 PPARαis rare, some evidences prove that miRNAs are involved in the PPARαsignal pathway. It is envisaged that investigating the roles of miRNAs in the PPARαsignal pathway could not only advance our understanding of the protective effect of PPARαon kidneys, but might also provide new therapeutic targets for acute nephrosis. The primary goal of this project was to investigate the detailed protective mechanism of PPARαon gentamicin-induced acute renal failure. We will focus on the roles of PLC, Akt and miRNAs in the anti-apoptotic effect of PPARαin rat renal tubular cells (NRK-52E) and animal models. By using 2-D gel analysis and micro-array analysis, the specific proteins and miRNAs involved in the protective mechanism of PPARαwill be identified. In this 3-year project, the PPARα-associated PLC and Akt signaling pathways as well as PPARα-influenced miRNAs will be investigated in vivo and in vitro. The specific aims of this project are listed as below: 1. To investigate the role of PLC signaling pathway in anti-apoptotic effect of PPARα. 2. To investigate the role of PI3K/Akt signaling pathway in anti-apoptotic effect of PPARα. 3. To investigate specific miRNAs involved in anti-apoptotic effect of PPARα. 4. To identify the target genes for the specific miRNAs in the protective mechanism of PPARα.