Abstract
Notwithstanding controversies over the role of epithelial to mesenchymal transition in the pathogenesis of renal disease, the last decade has witnessed a revolution in our understanding of the regulation of renal cell plasticity. Significant parallels undoubtedly exist between ontogenic processes and the initiation and propagation of damage in the diseased kidney as evidenced by the reactivation of developmental programmes of gene expression, in particular with respect to TGFβ superfamily signaling. Indeed, multiple signaling pathways converge on a complex transcriptional regulatory nexus that additionally involves epigenetic activator and repressor mechanisms and microRNA regulatory networks that control renal cell plasticity. It is becoming increasingly apparent that differentiated cells can acquire an undifferentiated state akin to “stemness” which is leading us towards new models of complex cell behaviors and interactions. Here we discuss the latest findings that delineate new and novel interactions between this transcriptional regulatory network and highlight a hitherto poorly recognized role for the Polycomb Repressive Complex (PRC2) in the regulation of renal cell plasticity. A comprehensive understanding of how external stimuli interact with the epigenetic control of gene expression, in normal and diseased contexts, establishes a new therapeutic paradigm to promote the resolution of renal injury and regression of fibrosis.
Highlights
Epithelial to Mesenchymal Transition (EMT) is a unique biologic process that involves distinct molecular reprogramming and phenotypic changes characterized by a transition from polarized epithelial cells to scattered mesenchymal cells, leading to increased motility and invasion (Figure 1)
Type I EMT occurs during embryogenesis and leads to the formation of primary mesenchyma that will eventually turn into epithelia [2]; type II EMT is associated with wound healing, tissue regeneration, and organ fibrosis [3]; type III EMT is typical of metastatic tumors [4]
We have shown that the treatment of renal cells with a specific EZH2 inhibitor, blocks the TGFβ mediated epithelial dedifferentiation and the expression of genes associated with fibrosis
Summary
Epithelial to Mesenchymal Transition (EMT) is a unique biologic process that involves distinct molecular reprogramming and phenotypic changes characterized by a transition from polarized epithelial cells to scattered mesenchymal cells, leading to increased motility and invasion (Figure 1). Med. 2016, 5, 6 processes the cells adapt to micro-environmental stimuli by dynamic decisions that determine changes in microRNAs, transcription factors (TFs), and epigenetic modifiers of gene expression This network exists in a delicate balance that if perturbed can lead to mis-regulation of cell identity with potential pathogenic roles in myriad diseases, including cancer and renal fibrosis. EMT can be triggered by a number of different growth factors, prominent among which are the members of the Transforming growth factor (TGF)-β superfamily [9] This superfamily controls the fate of epithelial cells, with some of the cytokines belonging to the Bone Morphogenic Protein (BMP) family, in particular BMP-7, able to block and reverse EMT during renal injury [10]. A more comprehensive understanding of these processes will shed light on the regulatory pathways that govern cell identity and identify new therapeutic paradigms for the treatment and regression of renal disease
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