New insights into epithelial-mesenchymal transition in kidney fibrosis

Abstract

Epithelial-mesenchymal transition (EMT), a process by which differentiated epithelial cells undergo a phenotypic conversion that gives rise to the matrix-producing fibroblasts and myofibroblasts, is increasingly recognized as an integral part of tissue fibrogenesis after injury. However, the degree to which this process contributes to kidney fibrosis remains a matter of intense debate and is likely to be context-dependent. EMT is often preceded by and closely associated with chronic interstitial inflammation and could be an adaptive response of epithelial cells to a hostile or changing microenvironment. In addition to tubular epithelial cells, recent studies indicate that endothelial cells and glomerular podocytes may also undergo transition after injury. Phenotypic alteration of podocytes sets them in motion to functional impairment, resulting in proteinuria and glomerulosclerosis. Several intracellular signal transduction pathways such as TGFbeta/Smad, integrin-linked kinase (ILK) and Wnt/beta-catenin signaling are essential in controlling the process of EMT and presently are potential targets of antifibrotic therapy. This review highlights the current understanding of EMT and its underlying mechanisms to stimulate further discussion on its role, not only in the pathogenesis of renal interstitial fibrosis but also in the onset of podocyte dysfunction, proteinuria, and glomerulosclerosis.

Figure 1

Schematic presentation of the spectrum of podocyte responses after injury. Depending on the severity and duration of the injury, podocytes may respond to injurious stimuli in different ways, including hypertrophy, dedifferentiation and mesenchymal transition (EMT), detachment and apoptosis (depletion). EMT could be a primary pathway leading to podocyte dysfunction, proteinuria, and glomerulosclerosis in many common forms of proteinuric kidney diseases.

Figure 2

Simplified schematic shows major intracellular signaling networks and mediators involved in the regulation of EMT in the fibrotic kidney. Although EMT can be induced by a wide variety of stimuli and potentially involves a diverse array of intracellular mediators, three major signaling pathways (i.e., TGFβ/Smad, integrin/ILK, and Wnt/β-catenin signaling) are essential for conferring tubular and podocyte EMT. These pathways are intricately connected and integrated at different levels. See text for details.