Molecular Mechanisms of Renal Fibrosis

Vanderbilt University, Nashville TN

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Interstitial fibrosis is the final common pathway to end-stage renal disease. Kidney fibroblasts are principal contributors to this process, but little is known about where they come from or how they engage. To help study and better understand their role, we recently discovered a new protein called fibroblast-specific protein-I (FSP1). FSPI belongs to the S100 superfamily of intracellular calcium-binding proteins that regulate cytoskeletal-membrane interactions, cell growth, and differentiation. FSP1 is a high fidelity marker of fibroblasts and plays an instructive role in shaping their conversion from epithelium through a process called epithelial-mesenchymal transition (EMT). We plan to further explore the relationship between renal fibroblasts and adjacent epithelium using FSPl-based molecular and transgenic probes. In particular, we found an FTS-1/CArG box-binding site in the FSP1 promoter that not only confers fibroblast specificity but also identifies a group of other genes comprising the EMT transcriptome. A zinc-finger transcription factor identified by us and called CBF (CArG box binding factor) may be a good candidate for regulating EMT through those sites. We have also made a FSP1 +/+ GFP mouse that marks fibroblasts green to better identify, isolate, and map their fate during development, a FSP1 GFP/GFP knockin mouse to explore the role of FSP1 in regulating the mechanism of EMT, and a FSP1.Cre mouse to selectively unflox genes in fibroblasts whose functions are associated either with EMT or intercellular signaling (Tbr2 flox/flox , BMP4 flox/lacZ, cMet flox/flox, and Egfr flox/flox). The evaluation of these transgenic probes is likely to inform our future work by revealing, or selectively disturbing, important signals between renal fibroblasts and their adjacent epithelium during organogenesis or injury. Thus, our overall approach should advance understanding of fibroblasts in health and disease as well as the critical signals that shape their phenotype. This understanding may be key to learning how we can further manipulate their participation in renal fibrosis.