Matrix metalloproteinases(MMPs) are members of the neutral proteinase family. They were previously thought to be anti-fibrotic because of their ability to degrade and remodel of extracellular matrix. However, recent s...Matrix metalloproteinases(MMPs) are members of the neutral proteinase family. They were previously thought to be anti-fibrotic because of their ability to degrade and remodel of extracellular matrix. However, recent studies have shown that MMPs are implicated in initiation and progression of kidney fibrosis through tubular cell epithelial–mesenchymal transition(EMT) as well as activation of resident fibroblasts, endothelial-mesenchymal transition(Endo MT) and pericyte-myofibroblast transdifferentiation. Interstitial macrophage infiltration has also been shown to correlate with the severity of kidney fibrosis in various chronic kidney diseases. MMPs secreted by macrophages, especially MMP-9, hasbeen shown by us to be profibrotic by induction of tubular cells EMT. EMT is mainly induced by transforming growth factor-β(TGF-β). However, MMP-9 was found by us and others to be up-regulated by TGF-β1 in kidney tubular epithelial cells and secreted by activated macrophages, resulting in EMT and ultimately kidney fibrosis. Therefore, MMP-9 may serve as a potential therapeutic target to prevent kidney fibrosis in chronic kidney disease. This review, by a particular focus on EMT, seeks to provide a comprehensive understanding of MMPs, especially MMP-9, in kidney fibrosis.展开更多
The main threat to a kidney injury, whatever its cause and regardless of whether it is acute or chronic, is the initiation of a process of renal fibrogenesis, since fbrosis can auto-perpetuate and is of high prognosti...The main threat to a kidney injury, whatever its cause and regardless of whether it is acute or chronic, is the initiation of a process of renal fibrogenesis, since fbrosis can auto-perpetuate and is of high prognostic significance in individual patients. In the clinic, a decrease in glomerular fltration rate correlates better with tubulointerstitial damage than with glomerular injury. Accumulation of the extracellular matrix should not be isolated from other significant cellular changes occurring in the kidney, such as infiltration by infammatory cells, proliferation of myofbroblasts, obliteration of peritubular capillaries and atrophy of tubules. The aim of this review is to focus on tubular epithelial cells （TEC）, which, necessarily involved in the repair process, eventually contribute to accelerating fibrogenesis. In the context of injury, TEC rapidly exhibit phenotypic and functional changes that recall their mesenchymal origin, and produce several growth factors known to activate myofbroblasts. Because they are high-demanding energy cells, TEC will subsequently suffer from the local hypoxia that progressively arises in a microenvironment where the matrix increases and capillaries become rarifed. The combination of hypoxia and metabolic acidosis may induce a vicious cycle of sustained inflammation, at the center of which TEC dictate the rate of renal fbrogenesis.展开更多
文摘Matrix metalloproteinases(MMPs) are members of the neutral proteinase family. They were previously thought to be anti-fibrotic because of their ability to degrade and remodel of extracellular matrix. However, recent studies have shown that MMPs are implicated in initiation and progression of kidney fibrosis through tubular cell epithelial–mesenchymal transition(EMT) as well as activation of resident fibroblasts, endothelial-mesenchymal transition(Endo MT) and pericyte-myofibroblast transdifferentiation. Interstitial macrophage infiltration has also been shown to correlate with the severity of kidney fibrosis in various chronic kidney diseases. MMPs secreted by macrophages, especially MMP-9, hasbeen shown by us to be profibrotic by induction of tubular cells EMT. EMT is mainly induced by transforming growth factor-β(TGF-β). However, MMP-9 was found by us and others to be up-regulated by TGF-β1 in kidney tubular epithelial cells and secreted by activated macrophages, resulting in EMT and ultimately kidney fibrosis. Therefore, MMP-9 may serve as a potential therapeutic target to prevent kidney fibrosis in chronic kidney disease. This review, by a particular focus on EMT, seeks to provide a comprehensive understanding of MMPs, especially MMP-9, in kidney fibrosis.
文摘The main threat to a kidney injury, whatever its cause and regardless of whether it is acute or chronic, is the initiation of a process of renal fibrogenesis, since fbrosis can auto-perpetuate and is of high prognostic significance in individual patients. In the clinic, a decrease in glomerular fltration rate correlates better with tubulointerstitial damage than with glomerular injury. Accumulation of the extracellular matrix should not be isolated from other significant cellular changes occurring in the kidney, such as infiltration by infammatory cells, proliferation of myofbroblasts, obliteration of peritubular capillaries and atrophy of tubules. The aim of this review is to focus on tubular epithelial cells （TEC）, which, necessarily involved in the repair process, eventually contribute to accelerating fibrogenesis. In the context of injury, TEC rapidly exhibit phenotypic and functional changes that recall their mesenchymal origin, and produce several growth factors known to activate myofbroblasts. Because they are high-demanding energy cells, TEC will subsequently suffer from the local hypoxia that progressively arises in a microenvironment where the matrix increases and capillaries become rarifed. The combination of hypoxia and metabolic acidosis may induce a vicious cycle of sustained inflammation, at the center of which TEC dictate the rate of renal fbrogenesis.
