1,721,063 research outputs found
EMT and proteinuria as progression factors
No full textTubulointerstitial fibrosis is an integral part of the structural changes of the kidney in chronic progressive renal failure. The accumulation of the extracellular matrix in the tubulointerstitial space is mediated mainly by myofibroblasts. These are derived from resident interstitial fibroblasts, tubular epithelial cells, periadventitial cells, and possibly also mesenchymal stem cells and endothelial cells. Fibrosis is usually preceded by tubulointerstitial infiltration of mononuclear inflammatory cells. Proteinuria is one of several mechanisms of primary glomerular or vascular disease to transmit the disease process to the interstitial space. Increased protein filtration may have direct toxic effects on tubular epithelial cells, induce chemokine and cytokine secretion and result in increased expression of adhesion molecules, all contributing to the influx of mononuclear cells. Inflammatory cells in return secrete cytokines, which stimulate resident fibroblasts and tubular epithelial cells to differentiate into matrix-producing cells. The phenotypic conversion of primary epithelial cells into mesenchymal cells, termed epithelial-mesenchymal transition (EMT), has been studied in great detail in recent years. Several signal transduction pathways of this process have been clarified and may eventually result in novel therapeutic approaches. The severity of proteinuria and the extent of EMT have both been associated with the decline in renal function in clinical studies. Limiting proteinuria results in a slower decline of renal function deterioration, whereas reducing EMT has had beneficial effects in a number of animal studies, including those indicating reversal of fibrotic lesions. However, the association between proteinuria and EMT and vice versa is far from clear and has not been carefully studied
Potential methods to prevent interstitial fibrosis in renal disease
No full textAlmost all forms of end stage renal disease (ESRD) are characterised by progressive interstitital fibrosis and tubular atrophy. Since most forms of chronic renal failure are initiated by inflammatory processes, anti-inflammatory strategies can be successful, if initiated early, in preventing progression of the disease process. Unfortunately, in most cases the disease is only detected clinically following robust progression of interstitial fibrosis. In these patients, control of secondary risk factors, such as hypertension and hyperglycaemia, can slow the progression rate but cannot stop the process completely. Certainly, ACE inhibitors remain the mainstay of preserving renal function. However, additional therapies are needed for the effective treatment of progressive renal fibrosis. A number of compounds have shown some very potent antifibrotic properties in vitro and in vivo, and are currently undergoing further evaluation. This review discusses the most promising among them. However, few of the therapeutic agents discussed here have been tested clinically. Studies evaluating the potential of a number of these have just commenced whereas for many others clinical use is still many years away. However, some very promising reagents may enhance our clinical arsenal within a relatively short period of time
New insights into mechanisms of fibrosis in immune renal injury
No full textRenal fibrosis is the final common pathway for many kidney lesions that lead to chronic progressive organ failure. The tubulointerstitial space occupies up to 90% of kidney volume, indicating that pathological changes in that space can not be without functional significance. By analogy to wound healing, renal fibrogenesis can be divided arbitrarily into three phases: induction, inflammatory, and post-inflammatory phases. The latter phase is of particular importance, since its length often exceeds what would be required for healing. The induction phase is characterized by the infiltration of the tubulointerstitial space by mononuclear inflammatory cells. This influx is mediated by proinflammatory cytokines and chemokines often secreted by activated tubular epithelial cells. Subsequently, these infiltrating mononuclear cells stimulate a heterogeneous group of resident fibroblasts and tubular epithelial cells to undergo phenotypic conversion into activated fibroblasts that secrete abundant extracellular matrix. Tubular epithelial cells contribute to this process through epithelial-mesenchymal transition. During the inflammatory phase these activated fibroblasts are stimulated to produce collagenous matrix mainly by cytokines, such as TGF-beta1, EGF, ET-1, and FGF-2, which are secreted by inflammatory and injured somatic cells. Occasionally however, when inflammation subsides, the matrix synthesis in the post-inflammatory phase of renal fibrogenesis continues and may be more dependent on autocrine stimulation from resident renal cells such as remaining tubular epithelium. Eventually, the collagenous matrix of fibrogenesis destroys blood supply and the perimeter of viability for fibroblasts regresses to the point where scars become acellular.NHLBI NIH HHS [HL-68121]; NIDDK NIH HHS [DK-46282 R01
Role of fibroblast activation in inducing interstitial fibrosis
No full textTubulointerstitial fibrosis is an obligate finding in endstage diseased kidneys. Renal fibrosis is defined as excessive matrix deposition that leads to tissue destruction and impairment of renal function. This process is often independent of the initial underlying disease and is not self-limited, in contrast to normal wound healing. Fibroblasts are the main effector cells in fibrogenesis, and mainly contribute to increased synthesis of matrix components. Increased matrix production is preceeded by massive proliferation of fibroblasts. The transformation from quiescent interstitial cells to proliferating and excessively matrix-producing cells has been termed fibroblast activation, which includes functional implications as well as phenotypic changes such as the expression of ct-smooth muscle actin ("myofibroblasts"). Activation of fibroblasts typically occurs through four distinct mechanisms: stimulation by growth factors ("auto- and paracrine"), by direct cell-cell contacts, by extracellular matrix via integrins, and by environmental conditions such as hyperglycemia or hypoxia in renal disease. The crucial step though, that distinguishes wound healing from fibrosis, is the perpetuation of the activated state. The clarification of cellular events connected with fibrogenesis has led to new approaches for therapy. Direct targeting of fibroblasts, inhibition of matrix deposition and specific inhibition of fibroblast activation have proved successful in experimental models and thus may lead to new approaches in the treatment of progressive renal disease
CYCLOSPORINE A INDUCES EPITHELIAL MESENCHYMAL TRANSITION IN MURINE TUBULAR EPITHELIAL CELL LINES MAINLY BUT NOT EXCLUSIVELY VIA INDUCTION OF TRANSFORMING GROWTH FACTOR (TGF-beta 1)
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