Oncostatin M-induced effects on EMT in human proximal tubular cells: differential role of ERK signaling

2007 ◽  
Vol 293 (5) ◽  
pp. F1714-F1726 ◽  
Author(s):  
Verena Pollack ◽  
Rita Sarközi ◽  
Zoltan Banki ◽  
Elisabeth Feifel ◽  
Swantje Wehn ◽  
...  
Keyword(s):  
Collagen Type ◽  
Collagen Type I ◽  
Oncostatin M ◽  
Type I ◽  
Proximal Tubular Cells ◽  
Strong Concentration ◽  
Tubular Cells ◽  
Cell Scattering ◽  
Proximal Tubular ◽  
E Cadherin

Growing evidence suggests that a proportion of interstitial myofibroblasts detected during renal tubulointerstitial fibrosis originates from tubular epithelial cells by a process called epithelial-mesenchymal transition (EMT). The IL-6-type cytokine oncostatin M (OSM) has been recently implicated in the induction of EMT. We investigated OSM effects on the expression of both cell-cell contact proteins and mesenchymal markers and studied OSM-induced intracellular signaling mechanisms associated with these events in human proximal tubular cells. Human recombinant OSM attenuated the expression of N-cadherin, E-cadherin, and claudin-2 in human kidney-2 (HK-2) cells associated with the induction of HK-2 cell scattering in 3D collagen matrices. Conversely, expression of collagen type I, vimentin, and S100A4 was induced by OSM. OSM-stimulated cell scattering was inhibited by antibodies against gp130. Besides inducing phosphorylation of Stat1 and Stat3, OSM led to a strong concentration- and time-dependent phosphorylation of the mitogen-activated protein kinases ERK1, ERK2, and ERK5. MEK1/2 inhibitor U0126 (10 μM) blocked basal and OSM-induced ERK1/2 phosphorylation but not phosphorylation of either ERK5 or Stat1/3. Both synthetic MEK1/2 inhibitors U0126 and Cl-1040, when used at concentrations which inhibit ERK1/2 phosphorylation but not ERK5 phosphorylation, restored N-cadherin expression in the presence of OSM, inhibited basal claudin-2 expression, but did not affect either basal or OSM-inhibited E-cadherin expression or OSM-induced expression of collagen type I and vimentin. These results suggest that in human proximal tubular cells ERK1/2 signaling represents an important component of OSM's inhibitory effect on N-cadherin expression. Furthermore, functional ERK1/2 signaling is necessary for basal claudin-2 expression.

scholarly journals BMP1 inhibitor UK383,367 attenuates renal fibrosis and inflammation in CKD

2019 ◽  
Vol 317 (6) ◽  
pp. F1430-F1438 ◽  
Author(s):  
Mi Bai ◽  
Juan Lei ◽  
Shuqin Wang ◽  
Dan Ding ◽  
Xiaowen Yu ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Collagen Type ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Collagen Type I ◽  
Type I ◽  
Tubular Cells ◽  
Morphogenetic Protein ◽  
Proximal Tubular

Renal fibrosis is a key pathological phenomenon of chronic kidney disease (CKD) contributing to the progressive loss of renal function. UK383,367 is a procollagen C proteinase inhibitor that has been selected as a candidate for dermal antiscarring agents, whereas its role in renal fibrosis is unclear. In the present study, UK383,367 was applied to a CKD mouse model of unilateral ureteral obstruction (UUO) and cell lines of renal tubular epithelial cells (mouse proximal tubular cells) and renal fibroblast cells (NRK-49F cells) challenged by transforming growth factor-β1. In vivo, bone morphogenetic protein 1, the target of UK383,367, was significantly enhanced in UUO mouse kidneys and renal biopsies from patients with CKD. Strikingly, UK383,367 administration ameliorated tubulointerstitial fibrosis as shown by Masson’s trichrome staining in line with the blocked expression of collagen type I/III, fibronectin, and α-smooth muscle actin in the kidneys from UUO mice. Similarly, the enhanced inflammatory factors in obstructed kidneys were also blunted. In vitro, UK383,367 pretreatment inhibited the induction of collagen type I/III, fibronectin, and α-smooth muscle actin in both mouse proximal tubular cells and NRK-49F cells treated with transforming growth factor-β1. Taken together, these findings indicate that the bone morphogenetic protein 1 inhibitor UK383,367 could serve as a potential drug in antagonizing CKD renal fibrosis by acting on the maturation and deposition of collagen and the subsequent profibrotic response and inflammation.

scholarly journals C-peptide reverses TGF-β1-induced changes in renal proximal tubular cells: implications for treatment of diabetic nephropathy

2009 ◽  
Vol 296 (3) ◽  
pp. F614-F621 ◽  
Author(s):  
Claire E. Hills ◽  
Nawal Al-Rasheed ◽  
Nouf Al-Rasheed ◽  
Gary B. Willars ◽  
Nigel J. Brunskill
Keyword(s):  
Diabetic Nephropathy ◽  
Receptor Expression ◽  
Type I ◽  
Proximal Tubular Cells ◽  
C Peptide ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Mesenchymal Transformation ◽  
Tgf Β1 ◽  
E Cadherin

The crucial pathology underlying progressive chronic kidney disease in diabetes is tubulointerstitial fibrosis. Central to this process is epithelial-mesenchymal transformation (EMT) of proximal tubular epithelial cells driven by maladaptive transforming growth factor-β1 (TGF-β1) signaling. Novel signaling roles for C-peptide have recently been discovered with evidence emerging that C-peptide may mitigate microvascular complications of diabetes. We studied the potential for C-peptide to interrupt injurious TGF-β1 signaling pathways and thus block development of EMT in HK2 human kidney proximal tubular cells. Cells were incubated with TGF-β1 either alone or with C-peptide in low or high glucose. Changes in cell morphology, TGF-β1 receptor expression, vimentin, E-cadherin, and phosphorylated Smads were assessed. Luciferase reporters were used to assess Smad activity. The cytoskeleton was visualized by TRITC-phalloidin staining. The typical TGF-β1-stimulated, EMT-associated morphological alterations of proximal tubular cells, including increased vimentin expression, decreased E-cadherin expression, and cytoskeletal rearrangements, were prevented by C-peptide treatment. C-peptide also blocked TGF-β1-induced upregulation of expression of both type I and type II TGF-β1 receptors and attenuated TGF-β1-mediated Smad phosphorylation and Smad transcriptional activity. These effects of C-peptide were inhibited by pertussis toxin. The results demonstrate that C-peptide almost completely reversed the morphological changes in PT cells induced by TGF-β1 and suggest a role or C-peptide as a renoprotective agent in diabetic nephropathy.

scholarly journals Collagen type I-induced Smad-interacting protein 1 expression downregulates E-cadherin in pancreatic cancer

Oncogene ◽  
2006 ◽  
Vol 26 (16) ◽  
pp. 2381-2385 ◽  
Author(s):  
Y Imamichi ◽  
A König ◽  
T Gress ◽  
A Menke
Keyword(s):  
Pancreatic Cancer ◽  
Collagen Type ◽  
Collagen Type I ◽  
Type I ◽  
Interacting Protein ◽  
E Cadherin

scholarly journals Loss of Tubular Bone Morphogenetic Protein—7 in Diabetic Nephropathy

2001 ◽  
Vol 12 (11) ◽  
pp. 2392-2399 ◽  
Author(s):  
SHI-NONG WANG ◽  
JANINE LAPAGE ◽  
RAIMUND HIRSCHBERG
Keyword(s):  
Diabetic Nephropathy ◽  
Bone Morphogenetic Protein ◽  
Type I ◽  
Proximal Tubular Cells ◽  
Bone Morphogenetic Protein 7 ◽  
Tubular Cells ◽  
Morphogenetic Protein ◽  
Proximal Tubular ◽  
Bmp Antagonist ◽  
Renal Expression

Abstract. Bone morphogenetic protein—7 (BMP7), a member of the transforming growth factor—β (TGF—β) superfamily of cytokines, is highly expressed in renal tubules and generally promotes maintenance of epithelial phenotype. It was examined whether, during the evolution of experimental diabetic nephropathy, the renal expression of BMP7 and BMP7 receptors declines, and the hypothesis that loss of BMP7 activity is profibrogenic in proximal tubular cells was tested. Moreover,in vitrostudies in cultured proximal tubular cells were performed to examine putative mechanisms that cause these changes. At 15 wk of streptozotocin-induced diabetes, renal expression of BMP7 is declined by about half, and it decreased further by 30 wk to <10% of timed controls. Renal expression of the high-affinity BMP type II receptor and the type I receptor Alk2 (activin receptor—like kinase-2) decreased. Alk3 tended to decrease, but Alk6 remained unchanged. During the evolution of diabetic nephropathy, the secreted BMP antagonist gremlin increased substantially. In cultured tubular cells, TGF-β reduced BMP7 and Alk3 expression and increased gremlin but did not interrupt BMP7-induced activation of smad5 or Erk1 and -2. In contrast, BMP7 did not alter TGF-β expression. Neutralization of endogenous BMP7 in cultured proximal tubular cells raised the expression of fibronectin and tended to increase collagen α1III mRNA levels. In conclusion, in experimental diabetic nephropathy, renal tubular BMP7 and some of its receptors decreased and gremlin, a secreted BMP antagonist, increased. Some, but not all, of these changes are explained by increased TGF-β. The loss of BMP7 activityper seis profibrogenic in tubular cells.

scholarly journals Synergistic induction of CCL2/MCP-1 expression driven by oncostatin M and IL-1β in human proximal tubular cells depends on STAT3 and p65 NFκ B/RelA

2015 ◽  
Vol 3 (2) ◽  
pp. e12298 ◽  
Author(s):  
Rita Sarközi ◽  
Ulrike Corazza ◽  
Jan-Philipp Osterkamp ◽  
Markus Pirklbauer ◽  
Gert Mayer ◽  
...  
Keyword(s):  
Oncostatin M ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Synergistic Induction

Oncostatin M inhibits TGF-β1-induced CTGF expression via STAT3 in human proximal tubular cells

2012 ◽  
Vol 424 (4) ◽  
pp. 801-806 ◽  
Author(s):  
Rita Sarközi ◽  
Kathrin Flucher ◽  
Viktoria Maria Haller ◽  
Markus Pirklbauer ◽  
Gert Mayer ◽  
...  
Keyword(s):  
Oncostatin M ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Tgf Β1

scholarly journals Cyclosporin A stimulates transcription and procollagen secretion in tubulointerstitial fibroblasts and proximal tubular cells.

1990 ◽  
Vol 1 (6) ◽  
pp. 918-922
Author(s):  
G Wolf ◽  
P D Killen ◽  
E G Neilson
Keyword(s):  
Cyclosporin A ◽  
Gene Product ◽  
Transcriptional Activity ◽  
Type I ◽  
Renal Cells ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Procollagen Type ◽  
Procollagen Type I ◽  
Proximal Tubular

The brief study described in this report was undertaken to determine whether cyclosporin A had any direct effect on the expression of tubulointerstitial procollagens in cultured renal cells. Our findings indicate that murine tubulointerstitial fibroblasts secreted significantly more procollagen type I after the addition of cyclosporin A, whereas syngeneic proximal tubular cells expressed significantly more types I and IV procollagen after cyclosporin stimulation. These increases in procollagen gene product correlated concordantly with changes in the levels of cytoplasmic mRNA with procollagen-specific cDNA probes. Transfection of these fibroblasts and proximal tubular cells with chimeric gene constructs containing enhancer/promoter elements for alpha2(I) and alpha 1(IV) procollagen linked to a chloramphenicol acetyltransferase reporter gene indicates that the stimulatory effect of cyclosporin on procollagen expression depends, at least to some extent, on an increase in transcriptional activity.

Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1

2001 ◽  
Vol 114 (1) ◽  
pp. 111-118 ◽  
Author(s):  
V. Noe ◽  
B. Fingleton ◽  
K. Jacobs ◽  
H.C. Crawford ◽  
S. Vermeulen ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Cell Surface ◽  
Collagen Type ◽  
Cell Aggregation ◽  
Collagen Type I ◽  
Type I ◽  
Tissue Inhibitor Of Metalloproteinases ◽  
Dependent Cell ◽  
Mcf 7 ◽  
E Cadherin

The function of many transmembrane molecules can be altered by cleavage and subsequent release of their ectodomains. We have investigated ectodomain cleavage of the cell-cell adhesion and signal-transducing molecule E-cadherin. The E-cadherin ectodomain is constitutively shed from the surface of MCF-7 and MDCKts.srcC12 cells in culture. Release of the 80 kDa soluble E-cadherin fragment is stimulated by phorbol-12-myristate-13-acetate and is inhibited by overexpression of the tissue inhibitor of metalloproteinases-2. The metalloproteinases matrilysin and stromelysin-1 both cleave E-cadherin at the cell surface and release sE-CAD into the medium. The soluble E-cadherin fragment thus released inhibits E-cadherin functions in a paracrine way, as indicated by induction of invasion into collagen type I and inhibition of E-cadherin-dependent cell aggregation. Our results, therefore, suggest a novel mechanism by which metalloproteinases can influence invasion.

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