BMP-7 fails to attenuate TGF- 1-induced epithelial-to-mesenchymal transition in human proximal tubule epithelial cells

Dudas, Paul L.; Argentieri, Rochelle L.; Farrell, Francis X.

doi:10.1093/ndt/gfn662

Cited by 54 publications

(46 citation statements)

References 22 publications

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“…In parallel, CTGF (connective tissue growth factor) and CD44 were upregulated at 10 ng/ml and TGFBR1 (TGF-β receptor 1) was upregulated at 100 ng/ml. For comparison, the proinflammatory/profibrotic gene expression profile was also examined in the proximal tubule cells in response to TGF-β 1 , a well-described profibrotic mediator, at a concentration previously described to elicit a robust profibrotic epithelial-to-mesenchymal transition [9,10]. TGF-β 1 (3 ng/ml, 24 h) downregulated CDH1 transcript and upregulated CTGF , VIM (vimentin) and TGFB1 (TGF-β 1 ) transcript expression indicative of TGF-β 1 -induced EMT (epithelial-to-mesenchymal transition) (fig.…”

Section: Resultsmentioning

confidence: 99%

Proinflammatory/Profibrotic Effects of Interleukin-17A on Human Proximal Tubule Epithelium

Dudas¹,

Sague²,

Elloso³

et al. 2010

Nephron Exp Nephrol

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Background/Aims: Interleukin-17A (IL-17A) is a T cell-derived inflammatory cytokine that is upregulated during renal allograft rejection. The present study sought to further describe the IL-17A-mediated proinflammatory/profibrotic activity of proximal tubule epithelium that may contribute to allograft rejection. Methods: Immortalized (HK-2) and primary (HRPTEpiC) human proximal tubule epithelial cells were utilized for this study. Profibrotic gene alterations were examined by real-time quantitative PCR. Inflammatory mediator secretion was examined by multiplex bead-based detection of secreted proteins. Immunofluorescence microscopy and immunoblotting were utilized to examine alterations in junctional protein expression and cell morphology. Results: In HK-2 cells IL-17A significantly downregulated the expression of the proepithelial gene CDH1 (E-cadherin) while the proinflammatory/profibrotic genes CTGF, CD44 and TGFBR1 were significantly increased. IL-17A also increased the secretion of fractalkine, G-CSF, GM-CSF, VEGF, IL-6 and IL-8. In HRPTEpiC 100 ng/ml IL-17A upregulated the proinflammatory/profibrotic genes ACTA2, CCL2, CHMP1A, CTGF, FN1, IL6, FSP1, SMAD1, SMAD5, TGFB1 and TGFBR2 while treatment with a reduced concentration of IL-17A (0.1 ng/ml) decreased SMAD5, TGFB1 and PDGFRB expression. Changes in ZO-1 and E-cadherin protein expression and cell morphology were examined following IL-17A treatment as indicators of epithelial-to-mesenchymal transition. IL-17A decreased ZO-1 expression in HK-2 and HRPTEpiC; however, E-cadherin was only reduced in HK-2 cells. Neither HK-2 nor HRPTEpiC assumed an elongated, fibroblast-like morphology following IL-17A treatment. Conclusions: IL-17A directly mediates proximal tubule epithelial cell proinflammatory/profibrotic activity as demonstrated by the alteration in genes associated with extracellular matrix remodeling and cell-cell interaction, and stimulation of inflammatory mediator and immune cell chemoattractant secretion. Additionally, IL-17A may have a negative impact on barrier integrity as indicated by ZO-1 downregulation.

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Section: Resultsmentioning

confidence: 99%

Proinflammatory/Profibrotic Effects of Interleukin-17A on Human Proximal Tubule Epithelium

Dudas¹,

Sague²,

Elloso³

et al. 2010

Nephron Exp Nephrol

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“…In the adult, BMP-7 alleviates TGF-β-induced renal fibrosis [115] and antagonises TGF-β-induced Smad3-dependent EMT [116]. However, the mechanism remains elusive since BMP-7 is unable to negate TGF-β-induced EMT in human PTC, suggesting that the effects are region specific [117]. The extent by which BMP-7 blocks EMT therefore requires further clarification.…”

Section: Therapeutic Interventionmentioning

confidence: 99%

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

Hills

Squires

2011

Cytokine & Growth Factor Reviews

170

187

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Transforming Growth Factor-beta (TGF-β) is a pro-sclerotic cytokine widely associated with the development of fibrosis in diabetic nephropathy. Central to the underlying pathology of tubulointerstitial fibrosis is epithelial-to-mesenchymal transition (EMT), or the trans-differentiation of tubular epithelial cells into myofibroblasts. This process is accompanied by a number of key morphological and phenotypic changes culminating in detachment of cells from the tubular basement membrane and migration into the interstitium. Ultimately these cells reside as activated myofibroblasts and further exacerbate the state of fibrosis. A large body of evidence supports a role for TGF-β and downstream Smad signaling in the development and progression of renal fibrosis. Here we discuss a role for TGF-β as the principle effector in the development of renal fibrosis in diabetic nephropathy, focusing on the role of the TGF-β1 isoform and its downstream signaling intermediates, the Smad proteins. Specifically we review evidence for TGF-β1 induced EMT in both the proximal and distal regions of the nephron and describe potential therapeutic strategies that may target TGF-β1 activity.

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“…In the adult, BMP-7 alleviates TGF-β-induced renal fibrosis [63] and antagonises TGF-β-induced Smad3-dependent EMT [64]. However, the mechanism remains elusive since BMP-7 is unable to negate TGF-β-induced EMT in human PTC, suggesting that the effects of BMP-7 are region specific [65]. The extent to which BMP-7 blocks EMT requires further clarification.…”

Section: Therapeutic Interventionmentioning

confidence: 99%

TGF-β1-Induced Epithelial-to-Mesenchymal Transition and Therapeutic Intervention in Diabetic Nephropathy

Hills¹,

Squires²

2009

Am J Nephrol

177

156

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Background/Aims: Epithelial-to-mesenchymal cell transformation (EMT) is the trans-differentiation of tubular epithelial cells into myofibroblasts, an event underlying progressive chronic kidney disease in diabetes, resulting in fibrosis. Mainly reported in proximal regions of the kidney, EMT is now recognized as a key contributor to the loss of renal function throughout the nephron in diabetic nephropathy (DN). Concomitant upregulation of TGF-β in diabetes makes this pro-fibrotic cytokine an obvious candidate in the development of these fibrotic complications. This article reviews recent findings clarifying our understanding of the role of TGF-β and associated sub-cellular proteins in EMT. Methods: To understand the pathology of EMT and the role of TGF-β, we reviewed the literature using PubMed for English language articles that contained key words related to EMT, TGF-β and DN. Results: EMT and phenotypic plasticity of epithelial cells throughout the nephron involves cytoskeletal reorganization and de novo acquisition of classic mesenchymal markers. Concurrent downregulation of epithelial adhesion molecules results in a loss of function and decreased cell coupling, contributing to a loss of epithelial integrity. TGF-β1 is pivotal in mediating these phenotypic changes. Conclusion: TGF-β-induced EMT is a key contributor to fibrotic scar formation as seen in DN, and novel routes for future therapeutic intervention are discussed.

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BMP-7 fails to attenuate TGF- 1-induced epithelial-to-mesenchymal transition in human proximal tubule epithelial cells

Cited by 54 publications

References 22 publications

Proinflammatory/Profibrotic Effects of Interleukin-17A on Human Proximal Tubule Epithelium

Proinflammatory/Profibrotic Effects of Interleukin-17A on Human Proximal Tubule Epithelium

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

TGF-β1-Induced Epithelial-to-Mesenchymal Transition and Therapeutic Intervention in Diabetic Nephropathy

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