| BackgroundCommon diseases causing progressive chronic renal failure, whatever the initiating injury are associated with fibrosis. Although these chronic tubulointerstitial changes have long been known to closely parallel a decline in renal function, and to have prognostic significance, their genesis and role in progression have received little attention until relatively recently. Over the past few years interest, initially focused on glomerular sclerosis as the major factor in progressive renal failure, has shifted towards the pathogenesis and role of tubulointerstitial changes in renal functional decline, and accordingly to whether interference with the mechanisms may be one way of slowing renal functional deterioration. Tubulointerstitial fibrosis is the final common pathway to end-stage renal disease.Understanding the mechanisms of tubulointerstitial fibrosis is essential in establishing novel therapeutic strategies for the prevention or arrest of progressive kidney diseases. Inflammation of the tubulointerstitial compartment, leading to fibrosis, is a major factor in the progressive loss of renal function in patients with a wide variety of kidney diseases. About 80% of the total kidney is composed of tubule epithelial cells and cells within the interstitial space. Most of the nonepithelial cells are associated with the rich vascular network of the kidney. There are also a small number of resident mononuclear cells and fibroblasts. A model of renal fibrosis that encompasses many aspects of other models of kidney disease is unilateral ureteral obstruction (UUO). Recent studies indicate that transforming growth factor-β (TGF-β) is linked to many of the cellular and molecular changes of renal tubulointerstitial fibrosis, one that emphasizes theroles of epithelial-mesenchymal transition (EMT) and cellular activation.Irrespective of the initial causes, interstitial fibrosis is a remarkably monotonous process characterized by de novo activation of a-smooth muscle actin (a-SMA)-positive myofibroblasts, the principal effecter cells that are responsible for the excess deposition of interstitial ECM under pathologic conditions. In this sense, a possible key to an effective therapy for CKD is to find a strategy that inhibits the activation of renal myofibroblasts in diseased kidney. Similarly, several studies have indicated that administration of renotrophic factors, such as insulin-like growth factor, hepatocyte growth factor, and bone morphogenic protein-7, can ameliorate fibrotic kidney disease.Tubular EMT, by definition, is a process in which renal tubular cells lose their epithelial phenotype and acquire new characteristic features of mesenchyme. This model of EMT process is largely based on detailed studies of phenotypic alterations in cultured tubular epithelial cells after stimulation with TGF-β1 and in renal tubular epithelia after obstructive injury. Despite that, it only represents an initial attempt to understand the complex process of EMT and is certainly subjected to any modifications. Nevertheless, it appears clear that EMT is an orchestrated process that depends on many intricate interactions between extrinsic regulators and intracellular mediators. EMT is regulated by numerous growth factors, cytokines, hormones, and extracellular cues in different ways. Of the many factors identified, the chief one perhaps is profibrotic TGF-β1. Induction of EMT may be a major pathway of TGF-β1 that leads to interstitial fibrosis under pathologic conditions.Notch signaling is a highly conserved mechanism used by multicellular animals to specify cell fate decisions during the formation of complex structures such as the kidney. A number ofstudies have recently identified requirements for Notch signaling during kidney organogenesis and tissue repair. A recent microarray survey of transcriptional changes in human keratinocytes exposed to TGF-β1 identified several components of the Notch pathway, including the basic helix-loop-helix transcription factor Hes-1 and Hey-1, a direct target of Notch signaling.To more fully unde...
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