Transforming Growth Factor-β, Basement Membrane, and Epithelial-Mesenchymal Transdifferentiation: Implications for Fibrosis in Kidney Disease

Abstract

Interstitial fibrosis is characteristic of many clinical entities including diabetes, ureteral obstruction, transplant rejection, and glomerulonephritis. 1 The interstitial fibrosis that accompanies renal disease is a complex process involving derangements in both the synthesis and degradation of collagen and other extracellular matrix proteins. Cellular sources of the extracellular matrix laid down during the development of interstitial fibrosis include fibroblasts and infiltrating macrophages. 1 The fibroblasts may be resident renal fibroblasts, fibroblasts that migrate into the kidney from external sources, or a specialized population of fibroblasts known as myofibroblasts. 2 Furthermore, recent evidence suggests that during renal injury, renal epithelial cells may transform into fibroblasts in a process known as epithelial-mesenchymal transdifferentiation (EMT). 3,4 The synthesis and processing of extracellular matrix that malfunction in fibrosis are under the complex control of many cytokines and other factors. 1 One cytokine in particular that has been implicated in fibrotic disease, both in the kidney and in other tissues, is transforming growth factor-β (TGF-β). In the accompanying article “Renal Fibrosis: Collagen Composition and Assembly Regulates Epithelial-Mesenchymal Transdifferentiation,” by Zeisberg and colleagues 5 in this issue of The American Journal of Pathology, Zeisberg and co-workers use murine renal cell lines in culture to demonstrate that the integrity of basement membrane collagen has a significant effect on EMT in vitro. They further demonstrate that when basement membrane assembly is disrupted, the production of TGF-β is up-regulated. In this article we will discuss the emerging role of EMT in fibrosis and its regulation, both in vitro and in vivo, with emphasis on effects of TGF-β and collagen IV.