Epithelial mesenchymal transdifferentiation (EMT) in the proximal tubule presumably has long-term detrimental consequences for kidney function. It sets the stage for various degrees of tubulointerstitial scarring that ultimately may be responsible for reducing the amount of functional kidney tissue and kidney function. It is notable that tubulointerstitial fibrosis, the end-product of EMT, characterizes nearly all forms of chronic progressive kidney disease from glomerular diseases to tubulointerstitial nephropathies to chronic allograft nephropathy. Therefore, increasing our understanding of the early aspects of this process is key towards developing early therapeutic interventions. This proposal focuses on the cellular events that may be occurring in EMT and uses a model that can discriminate between direct and feedback effects of a known mediator of EMT, TGF-beta 1. We hypothesize that TGF-beta 1 activates one, if not more, signaling pathways to initiate and perpetuate EMT. Our proposal attempts to dissect out which TGF-beta 1- associated signaling pathway is integral to EMT through straightforward pharmacologic analyses and through the use of a novel class of therapeutic agents, peptide aptamers that target TGF-beta 1 signaling molecules. However, a simple signaling survey may not account for the complexity of EMT in proximal tubule cells. Rather, a perpetuation of TGF-beta l's effects through persistent endogenously generated autocrine TGF-beta 1 may be the lynchpin of EMT in these cells. We can compare TGF-beta 1-mediated progression through EMT in wild-type and TGF-beta 1 knockout proximal tubule epithelial cells to assess whether this hypothesis is valid. These studies, though preliminary and, in some respects, screening in nature, represent a key piece of knowledge that can propel investigations forward in attempting to alter EMT in proximal tubule epithelial cells and potentially preserve functional kidney tissue.
| Das, Shreyas; Becker, Bryan N; Hoffmann, F Michael et al. (2009) Complete reversal of epithelial to mesenchymal transition requires inhibition of both ZEB expression and the Rho pathway. BMC Cell Biol 10:94 |
| Cui, Qiqi; Lim, Sang Kyun; Zhao, Bryan et al. (2005) Selective inhibition of TGF-beta responsive genes by Smad-interacting peptide aptamers from FoxH1, Lef1 and CBP. Oncogene 24:3864-74 |
