Cytokines in Epithelial-Mesenchymal Transition: A New Insight Into Obstructive Nephropathy

Abstract

Epithelial-mesenchymal transition is a cellular mechanism that has long been recognized as a central feature of normal development. However, increasing evidence implicates epithelial-mesenchymal transition in the pathophysiology of tubulointerstitial fibrosis and chronic renal disease. Recent insights into the molecular events and intrinsic signaling pathways that are active during epithelial-mesenchymal transition have evoked novel therapeutic strategies aimed at halting the onset and progression of chronic renal fibrosis.

Involvement of matrix metalloproteinase-2 in the development of renal interstitial fibrosis in mouse obstructive nephropathy

“…[1][2][3][4][5][6][7][8][9][10][11][12] Damaged tubular epithelial cells have mesenchymal phenotype through EMT, and migrate into interstitium. [7][8][9][10][11][12] Indeed, one recent study using a gGTLacZ transgenic mice, which allows the indisputable identification of cells derived from proximal tubular epithelium in the kidney, reported that more than one-third of renal interstitial fibroblasts were derived from renal tubular epithelium through EMT. 28 MMP-2 and MMP-9, which mediate TBM degradation, are considered a critical event in renal EMT.…”

“…[4][5][6] Recent studies have emphasized the potential role of epithelial-tomesenchymal transition (EMT) in the development of renal interstitial fibrosis. [7][8][9][10][11][12] Tubular epithelial cells can acquire a mesenchymal phenotype after several injuries, enhance migratory capacity enabling them to transit from the renal tubular microenvironment into the interstitial space, and contribute to the development of renal fibrosis as ECMproducing myofibroblasts. The role of EMT in renal fibrogenesis has been suggested in several studies of cultured cells, animal models of kidney diseases, and human nephropathies and kidney transplantation, [7][8][9][10][11][12] although several recent studies also demonstrate the doubt on this mechanism as a major contributor to renal fibrosis.…”

“…[7][8][9][10][11][12] Tubular epithelial cells can acquire a mesenchymal phenotype after several injuries, enhance migratory capacity enabling them to transit from the renal tubular microenvironment into the interstitial space, and contribute to the development of renal fibrosis as ECMproducing myofibroblasts. The role of EMT in renal fibrogenesis has been suggested in several studies of cultured cells, animal models of kidney diseases, and human nephropathies and kidney transplantation, [7][8][9][10][11][12] although several recent studies also demonstrate the doubt on this mechanism as a major contributor to renal fibrosis. [13][14][15] Matrix metalloproteinases (MMPs) are a family of zincdependent proteases responsible for ECM turnover as well as degradation of bioactive proteins.…”

Suramin Inhibits Renal Fibrosis in Chronic Kidney Disease

“…5,7,38 To determine the effect of suramin on expression of these cytokines, we measured their expression levels in the fibrotic kidney of animals treated or untreated with suramin using quantitative real-time PCR. Figure 9 shows that all of these cytokines were increased after obstructive injury; suramin treatment decreased expression levels of TNF-␣, IL-1␤, and ICAM-1 but not MCP-1.…”

BMP6 reverses TGF-β1-induced changes in HK-2 cells: implications for the treatment of renal fibrosis

“…This phenotypic conversion involves de novo synthesis of α-smooth muscle actin (α-SMA), a downregulation of E-cadherin, the acquisition of a spindle-like morphology, a disruption of the tubular basement membrane, the production of matrix proteins, and an enhanced cell migration and invasion capacity [3] . Transforming growth factor β1 (TGF-β1) plays a crucial role in the initiation and progression of renal fibrosis [4] . In response to TGF-β1, tubular epithelial cells can transdifferentiate into myofibroblasts via an EMT process.…”