scholarly journals The differential role of Smad2 and Smad3 in the regulation of pro-fibrotic TGFβ1 responses in human proximal-tubule epithelial cells

2005 ◽  
Vol 393 (2) ◽  
pp. 601-607 ◽  
Author(s):  
Mysore K. Phanish ◽  
Nadia A. Wahab ◽  
Paul Colville-Nash ◽  
Bruce M. Hendry ◽  
Mark E. C. Dockrell
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Proximal Tubule ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Smooth Muscle Actin ◽  
Tissue Growth ◽  
Matrix Metalloproteinase 2 ◽  
Renal Diseases ◽  
E Cadherin

In chronic renal diseases, progressive loss of renal function correlates with advancing tubulo-interstitial fibrosis. TGFβ1-Smad (transforming growth factor-β1–Sma and Mad protein) signalling plays an important role in the development of renal tubulo-interstitial fibrosis. Secretion of CTGF (connective-tissue growth factor; CCN2) by PTECs (proximal-tubule epithelial cells) and EMT (epithelial–mesenchymal transdifferentiation) of PTECs to myofibroblasts in response to TGFβ are critical Smad-dependent events in the development of tubulo-interstitial fibrosis. In the present study we have investigated the distinct contributions of Smad2 and Smad3 to expression of CTGF, E-cadherin, α-SMA (α-smooth-muscle actin) and MMP-2 (matrix-metalloproteinase-2) in response to TGFβ1 treatment in an in vitro culture model of HKC-8 (transformed human PTECs). RNA interference was used to achieve selective and specific knockdown of Smad2 and Smad3. Cellular E-cadherin, α-SMA as well as secreted CTGF and MMP-2 were assessed by Western immunoblotting. TGFβ1 treatment induced a fibrotic phenotype with increased expression of CTGF, MMP-2 and α-SMA, and decreased expression of E-cadherin. TGFβ1-induced increases in CTGF and decreases in E-cadherin expression were Smad3-dependent, whereas increases in MMP-2 expression were Smad2-dependent. Increases in α-SMA expression were dependent on both Smad2 and Smad3 and were abolished by combined knockdown of both Smad2 and Smad3. In conclusion, we have demonstrated distinct roles for Smad2 and Smad3 in TGFβ1-induced CTGF expression and markers of EMT in human PTECs. This can be of therapeutic value in designing targeted anti-fibrotic therapies for tubulo-interstitial fibrosis.

Mesenchymal transition in kidney collecting duct epithelial cells

2008 ◽  
Vol 294 (5) ◽  
pp. F1238-F1248 ◽  
Author(s):  
Larissa Ivanova ◽  
Michael J. Butt ◽  
Douglas G. Matsell
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Transforming Growth Factor ◽  
Collecting Duct ◽  
Smooth Muscle Actin ◽  
Organ Damage ◽  
Transforming Growth Factor Β1 ◽  
Mesenchymal Transition ◽  
E Cadherin

Progressive organ damage due to tissue scarring and fibrosis is a paradigm shared by numerous human diseases including chronic kidney disease. The purpose of this study was to confirm the hypothesis that collecting duct (CD) epithelial cells can undergo mesenchymal transition (EMT) in vitro. The mechanism by which CDs undergo EMT is complex and involves both early and late cellular events. Early events include rapid insulin-like growth factor (IGF)-induced Akt and GSK-3β phosphorylation, associated with early disruption of E-cadherin-β-catenin membrane colocalization, with translocation of E-cadherin to endosomes, with translocation of β-catenin to the nucleus, and with an increase in Snail expression. Transforming growth factor-β1, on the other hand, induced early activation of Smad3 and its translocation to the nucleus, Erk1/2 phosphorylation, and early disruption of membrane E-cadherin localization. The late consequences of these events included a phenotypic transformation of the cells to a mesenchymal morphology with associated increase in vimentin and α-smooth muscle actin protein expression and a decrease in total cellular E-cadherin expression, detectable as early as 24 h after stimulation.

scholarly journals Blockage of Tubular Epithelial to Myofibroblast Transition by Hepatocyte Growth Factor Prevents Renal Interstitial Fibrosis

2002 ◽  
Vol 13 (1) ◽  
pp. 96-107
Author(s):  
Junwei Yang ◽  
Youhua Liu
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Smooth Muscle Actin ◽  
Tubular Epithelial Cells ◽  
Renal Interstitial Fibrosis ◽  
Phenotypic Transition ◽  
Hepatocyte Growth

ABSTRACT. Activation of α-smooth muscle actin–positive myofibroblast cells is a key event in the progression of chronic renal diseases that leads to end-stage renal failure. Although the origin of these myofibroblasts in the kidney remains uncertain, emerging evidence suggests that renal myofibroblasts may derive from tubular epithelial cells by a process of epithelial to mesenchymal transition. It was demonstrated that hepatocyte growth factor (HGF) exhibited a remarkable ability to block this phenotypic transition both in vitro and in vivo. HGF abrogated the α-smooth muscle actin expression and E-cadherin depression triggered by transforming growth factor-β1 in tubular epithelial cells in a dose-dependent manner. HGF also blocked morphologic transformation of tubular epithelial cells and inhibited the expression and extracellular deposition of fibronectin. In a mouse model of renal fibrosis disease induced by unilateral ureteral obstruction, transforming growth factor-β type I receptor expression was specifically increased in renal tubules, and myofibroblastically phenotypic transition of the tubules was evident in vivo. Remarkably, injections of exogenous HGF blocked myofibroblast activation and drastically prevented renal interstitial fibrosis in the obstructed kidneys. These results suggest that tubular epithelial to myofibroblast conversion may play an important role in the pathogenesis of renal fibrosis and that blocking this phenotypic transition could provide a novel therapeutic strategy for the treatment of fibrotic diseases.

scholarly journals Regulation of Cellular Senescence Is Independent from Profibrotic Fibroblast-Deposited ECM

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1628
Author(s):  
Kaj E. C. Blokland ◽  
Habibie Habibie ◽  
Theo Borghuis ◽  
Greta J. Teitsma ◽  
Michael Schuliga ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cellular Senescence ◽  
Transforming Growth Factor ◽  
Cell Function ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β1 ◽  
Tissue Growth ◽  
Alveolar Epithelial Cells ◽  
Lung Fibroblasts ◽  
Alpha Smooth Muscle Actin

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with poor survival. Age is a major risk factor, and both alveolar epithelial cells and lung fibroblasts in this disease exhibit features of cellular senescence, a hallmark of ageing. Accumulation of fibrotic extracellular matrix (ECM) is a core feature of IPF and is likely to affect cell function. We hypothesize that aberrant ECM deposition augments fibroblast senescence, creating a perpetuating cycle favouring disease progression. In this study, primary lung fibroblasts were cultured on control and IPF-derived ECM from fibroblasts pretreated with or without profibrotic and prosenescent stimuli, and markers of senescence, fibrosis-associated gene expression and secretion of cytokines were measured. Untreated ECM derived from control or IPF fibroblasts had no effect on the main marker of senescence p16Ink4a and p21Waf1/Cip1. However, the expression of alpha smooth muscle actin (ACTA2) and proteoglycan decorin (DCN) increased in response to IPF-derived ECM. Production of the proinflammatory cytokines C-X-C Motif Chemokine Ligand 8 (CXCL8) by lung fibroblasts was upregulated in response to senescent and profibrotic-derived ECM. Finally, the profibrotic cytokines transforming growth factor β1 (TGF-β1) and connective tissue growth factor (CTGF) were upregulated in response to both senescent- and profibrotic-derived ECM. In summary, ECM deposited by IPF fibroblasts does not induce cellular senescence, while there is upregulation of proinflammatory and profibrotic cytokines and differentiation into a myofibroblast phenotype in response to senescent- and profibrotic-derived ECM, which may contribute to progression of fibrosis in IPF.

Transforming growth factor-β2-mediated mesenchymal transition in lens epithelial cells is repressed in the absence of RAGE

2021 ◽  
Vol 478 (12) ◽  
pp. 2285-2296
Author(s):  
Mi-Hyun Nam ◽  
Mina B. Pantcheva ◽  
Johanna Rankenberg ◽  
Ram H. Nagaraj
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Knockout Mice ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Lens Epithelial Cells ◽  
Wild Type ◽  
Mesenchymal Transition ◽  
Smad Signaling ◽  
Transforming Growth Factor Β2

Transforming growth factor-β2 (TGFβ2)-mediated epithelial to mesenchymal transition (EMT) in lens epithelial cells (LECs) has been implicated in fibrosis associated with secondary cataracts. In this study, we investigated whether the receptor for advanced glycation end products (RAGE) plays a role in TGFβ2-mediated EMT in LECs. Unlike in the LECs from wild-type mice, TGFβ2 failed to elicit an EMT response in LECs from RAGE knockout mice. The lack of RAGE also diminished TGFβ2-mediated Smad signaling. In addition, treatment with TGFβ2 increased IL-6 levels in LECs from wild-type mice but not in those from RAGE knockout mice. Treatment of human LECs with the RAGE inhibitor FPS-ZM1 reduced TGFβ2-mediated Smad signaling and the EMT response. Unlike that in wild-type lenses, the removal of fiber cell tissue in RAGE knockout lenses did not result in elevated levels of α-smooth muscle actin (α-SMA), fibronectin (FN), and integrin β1 in capsule-adherent LECs. Taken together, these results suggest that TGFβ2 signaling is intricately linked to RAGE. Targeting RAGE could be explored as a therapeutic strategy against secondary cataracts.

Fibroblasts of rabbit kidney in culture. II. Paracrine stimulation of papillary fibroblasts by PDGF

1991 ◽  
Vol 261 (2) ◽  
pp. F292-F299 ◽  
Author(s):  
A. Knecht ◽  
L. G. Fine ◽  
K. S. Kleinman ◽  
H. P. Rodemann ◽  
G. A. Muller ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Conditioned Medium ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Collecting Duct ◽  
Rabbit Kidney ◽  
Fibroblast Growth ◽  
Igf I

To examine the role of tubulointerstitial cell interaction in the regulation of fibroblast growth, fibroblasts from the rabbit renal cortex (CF) and papilla (PF) were cocultured with epithelial cells from the same tissue location. Inner medullary collecting duct epithelial cells (IMCDE) or IMCDE-conditioned medium stimulated DNA synthesis in PF, whereas proximal tubule epithelium (PTE) had no effect on the proliferation of CF. PF and CF showed a similar mitogenic response to exogenous epidermal growth factor and insulin-like growth factor 1 (IGF-I). Transforming growth factor-beta 1 inhibited growth of both cell types, and basic fibroblast growth factor (bFGF) had no effect on proliferation of either cell type. In contrast, platelet-derived growth factor (PDGF) was a potent mitogen for PF but was only weakly mitogenic for CF. Both CF and PF expressed a similar number of a single-affinity class of PDGF receptors (Kd, 2-4 x 10(-10) M). Assay for growth factor activity in conditioned medium from IMCDE and PTE showed that only IMCDE produced detectable PDGF. IMCDE-stimulated proliferation of PF was partially blocked by an antibody to PDGF, whereas antibodies to IGF-I had no neutralizing effect. The data suggest a role for PDGF in the regulation of interstitial fibroblast proliferation by IMCDE in the renal papilla. This paracrine system may be important in the pathogenesis of some forms of interstitial fibrosis of the kidney.

scholarly journals Hepatoprotective Effect of the Fruits of Polygonum orientale L. Against Carbon Tetrachloride-Induced Liver Fibrosis in Mice

2020 ◽  
Vol 15 (11) ◽  
pp. 1934578X2097150
Author(s):  
Yung-Jia Chiu ◽  
Kun-Chang Wu ◽  
Jen-Chieh Tsai ◽  
Chun-Pin Kao ◽  
Jung Chao ◽  
...  
Keyword(s):  
Carbon Tetrachloride ◽  
Growth Factor ◽  
Liver Injury ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Serum Levels ◽  
Hepatoprotective Activity ◽  
Tissue Growth ◽  
Factor Α

The aim of this study was to evaluate the hepatoprotective effects of the fruits of Polygonum orientale L. (POE) against fibrosis in carbon tetrachloride (CCl4)-induced liver injury. Bioactive components of POE were identified using liquid chromatography (LC)-mass spectrometry (MS)/MS by comparison with standards. Treatment with either silymarin (200 mg/kg) or POE (0.5 and 1.0 g/kg) caused significant decreases in the serum levels of enzymes and reduced the extent of liver lesions and fibrosis in histological analysis. POE (0.5 and 1.0 g/kg) decreased the levels of malondialdehyde, nitric oxide, proinflammatory cytokines (ie, tumor necrosis factor-α, interleukin [IL]-1β, and IL-6), an inflammatory cytokine (ie, cyclooxygenase-2), a profibrotic cytokine (ie, transforming growth factor-β), and fibrosis-related proteins (ie, connective tissue growth factor and α-smooth muscle actin) in the liver and enhanced the activities of the antioxidative enzymes superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. Quantitative analysis of the active constituents in POE revealed an extract composition of 3.4 mg/g of protocatechuic acid, 20.8 mg/g of taxifolin, and 5.6 mg/g of quercetin. We have demonstrated that the hepatoprotective mechanisms of POE are likely to be associated with the decrease in inflammatory cytokines by increasing the activities of antioxidant enzymes. Our findings provide evidence that POE possesses a hepatoprotective activity to ameliorate chronic liver injury.

scholarly journals A Herbal Formula, CGXII, Exerts Antihepatofibrotic Effect in Dimethylnitrosamine-Induced SD Rat Model

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Hyo-Seon Kim ◽  
Hyeong-Geug Kim ◽  
Hye-Won Lee ◽  
Sung-Bae Lee ◽  
Jin-Seok Lee ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Total Body Weight ◽  
Protein Carbonyl ◽  
Tissue Growth ◽  
Hepatic Tissue ◽  
Histopathological Analysis ◽  
Sprague Dawley ◽  
Serum Aspartate Aminotransferase

We aimed to evaluate the antihepatofibrotic effects of CGXII, an aqueous extract which is composed of A. iwayomogi, A. xanthioides, and S. miltiorrhiza, against dimethylnitrosamine- (DMN-) induced hepatofibrosis. Male Sprague Dawley rats were intraperitoneally injected with 10 mg/kg of DMN for 4 weeks (three consecutive days weekly). Rats were orally given distilled water, CGXII (50 or 100 mg/kg), or dimethyl dimethoxy biphenyl dicarboxylate (50 mg/kg) daily. DMN injection caused substantial alteration of total body weight and liver and spleen mass, whereas they were notably normalized by CGXII. CGXII treatment also markedly attenuated the elevation of serum aspartate aminotransferase and alanine aminotransferase levels, hepatic lipid peroxidation, and protein carbonyl contents. Collagen accumulation in hepatic tissue evidenced by histopathological analysis and quantitative assessment of hepatic hydroxyproline was ameliorated by CGXII. Immunohistochemistry analysis revealed decreased α-smooth muscle actin supporting the antihepatofibrotic effect of CGXII. The profibrogenic cytokines transforming growth factor-β, platelet-derived growth factor-β, and connective tissue growth factor were increased by DMN injection. Administration of CGXII normalized the protein and gene expression levels of these cytokines. Our findings suggest that CGXII lowers the levels of profibrogenic cytokines and thereby exerts antifibrotic effects.

scholarly journals Distribution of transforming growth factor-beta 1, fibronectin, and smooth muscle actin in asbestos-induced pulmonary fibrosis in rats.

1994 ◽  
Vol 42 (8) ◽  
pp. 1061-1070 ◽  
Author(s):  
T D Perdue ◽  
A R Brody
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Smooth Muscle Actin ◽  
Muscle Actin ◽  
Strong Localization ◽  
Growth Factor Beta ◽  
Immunohistochemical Techniques

We are studying the development of fibrogenic lesions in the lungs of rats exposed briefly to an aerosol of chrysotile asbestos fibers. This model of asbestosis has enabled us to establish very early cellular events at the specific locations where interstitial fibrosis will develop. These sites, the first alveolar duct bifurcations, are where the fibers are initially deposited and where macrophages first accumulate. In the studies presented here, we used immunohistochemical techniques to show that these macrophages exhibit strong localization of transforming growth factor-beta. In the adjacent developing fibrogenic lesions a clear increase in fibronectin staining was demonstrated and morphological analysis indicated a significant increase in amounts of smooth muscle actin. Such studies are essential in furthering our understanding of the distribution of potential mediators of the fibrogenic process and the cellular responses they elicit during the pathogenesis of disease.

Cytokines and L-arginine in renal injury and repair

1994 ◽  
Vol 267 (2) ◽  
pp. F197-F207 ◽  
Author(s):  
M. Ketteler ◽  
W. A. Border ◽  
N. A. Noble
Keyword(s):  
Growth Factor ◽  
Renal Disease ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Tissue Injury ◽  
Current Knowledge ◽  
Interstitial Fibrosis ◽  
Renal Diseases ◽  
Tgf Beta ◽  
Arginine Metabolism

Advances in molecular biology have identified cytokines as mediators of pathophysiological changes in chronic renal disease. Transforming growth factor-beta (TGF-beta) plays an important role in the pathogenesis of glomerular and interstitial fibrosis, whereas platelet-derived growth factor (PDGF) is involved in proliferative changes in chronic progressive renal diseases. Tumor necrosis factor-alpha and interleukins are expressed in experimental models of renal disease and are causes of inflammation and cell migration. Cytokines act by many different mechanisms, and one target of their action may be L-arginine metabolism. Since the discovery of the effector molecule nitric oxide (NO), generated from L-arginine, knowledge of this pathway has increased dramatically. It became evident that the L-arginine/NO pathway is of major importance in the regulation of hemodynamics and neurotransmission, in host defense against intracellular microorganisms, and in immunologic tissue injury. This pathway is induced by proinflammatory cytokines and possibly regulated by TGF-beta and PDGF. L-Arginine is also metabolized to L-ornithine, which can be processed to polyamines or to L-proline. As polyamines are important mediators of cell growth and L-proline is a substrate for collagen synthesis, both pathways, once activated, may be important in repair processes. It is likely that cytokines and L-arginine metabolism are interconnected and that both are involved in the inflammation, tissue repair, and fibrogenesis processes in the kidney. Dietary protein restriction in progressive renal diseases may substantially affect both systems. This review summarizes current knowledge about interactions of cytokines and L-arginine metabolism and the relevance to renal diseases.

Sign in / Sign up

Export Citation Format

Share Document