scholarly journals The Protective Effect of Fluorofenidone against Cyclosporine A-Induced Nephrotoxicity

2019 ◽  
Vol 44 (4) ◽  
pp. 656-668 ◽  
Author(s):  
Yang Chen ◽  
Nasui Wang ◽  
Qiongjing Yuan ◽  
Jiao  Qin ◽  
Gaoyun Hu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cyclosporine A ◽  
Caspase 3 ◽  
Renal Tubule ◽  
Annexin V ◽  
Type I ◽  
Tubulointerstitial Injury ◽  
Tubule Cells ◽  
Parp 1 ◽  
Tgf Β1

Background/Aims: Cyclosporine A (CsA) is an immunosuppressant drug that is used during organ transplants. However, its utility is limited by its nephrotoxic potential. This study aimed to investigate whether fluorofenidone (AKF-PD) could provide protection against CsA-induced nephrotoxicity. Methods: Eighty-five male Sprague-Dawley rats were divided into 5 groups: drug solvent, CsA, CsA with AKF-PD (250, 500 mg/kg/day), and CsA with pirfenidone (PFD, 250 mg/kg/day). Tubulointerstitial injury index, extracellular matrix (ECM) deposition, expression of type I and IV collagen, transforming growth factor (TGF)-β1, platelet-derived growth factor (PDGF), Fas ligand (FASL), cleaved-caspase-3, cleaved-poly(ADP-ribose) polymerase (PARP)-1, and the number of transferase-mediated nick end-labeling (TUNEL)-positive renal tubule cells were determined. In addition, levels of TGF-β1, FASL, cleaved-caspase-3, cleaved-PARP-1, and number of annexin V-positive cells were determined in rat proximal tubular epithelial cells (NRK-52E) treated with CsA (20 μmol/L), AKF-PD (400 μg/mL), PFD (400 μg/mL), and GW788388 (5 μmol/L). Results: AKF-PD (250, 500 mg/kg/day) significantly reduced tubulointerstitial injury, ECM deposition, expression of type I and IV collagen, TGF-β1, PDGF, FASL, cleaved-caspase-3, cleaved-PARP-1, and number of TUNEL-positive renal tubule cells in the CsA-treated kidneys. In addition, AKF-PD (400 μg/mL) significantly decreased TGF-β1, FASL, cleaved-caspase-3, and PARP-1 expression in NRK-52E cells and further reduced the number of annexin V-positive cells. Conclusion: AKF-PD protect kidney from fibrosis and apoptosis in CsA-induced kidney injury.

scholarly journals Therapeutic concentrations of cyclosporine A, but not FK506, increase P-glycoprotein expression in endothelial and renal tubule cells

1998 ◽  
Vol 54 (4) ◽  
pp. 1139-1149 ◽  
Author(s):  
Ingeborg A. Hauser ◽  
Michael Koziolek ◽  
Ulrich Hopfer ◽  
Frank Thévenod
Keyword(s):  
Cyclosporine A ◽  
Renal Tubule ◽  
P Glycoprotein ◽  
Tubule Cells

scholarly journals Autocrine Transforming Growth Factor-β1 Activation Mediated by Integrin αVβ3 Regulates Transcriptional Expression of Laminin-332 in Madin-Darby Canine Kidney Epithelial Cells

2010 ◽  
Vol 21 (21) ◽  
pp. 3654-3668 ◽  
Author(s):  
Jose V. Moyano ◽  
Patricia G. Greciano ◽  
Mary M. Buschmann ◽  
Manuel Koch ◽  
Karl S. Matlin
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Transforming Growth Factor ◽  
Integrin Αvβ3 ◽  
Type I ◽  
Madin Darby Canine Kidney ◽  
Epithelial Regeneration ◽  
Tgf Β1 ◽  
Darby Canine Kidney ◽  
Canine Kidney

Laminin (LM)-332 is an extracellular matrix protein that plays a structural role in normal tissues and is also important in facilitating recovery of epithelia from injury. We have shown that expression of LM-332 is up-regulated during renal epithelial regeneration after ischemic injury, but the molecular signals that control expression are unknown. Here, we demonstrate that in Madin-Darby canine kidney (MDCK) epithelial cells LM-332 expression occurs only in subconfluent cultures and is turned-off after a polarized epithelium has formed. Addition of active transforming growth factor (TGF)-β1 to confluent MDCK monolayers is sufficient to induce transcription of the LM α3 gene and LM-332 protein expression via the TGF-β type I receptor (TβR-I) and the Smad2–Smad4 complex. Significantly, we show that expression of LM-332 in MDCK cells is an autocrine response to endogenous TGF-β1 secretion and activation mediated by integrin αVβ3 because neutralizing antibodies block LM-332 production in subconfluent cells. In confluent cells, latent TGF-β1 is secreted apically, whereas TβR-I and integrin αVβ3 are localized basolaterally. Disruption of the epithelial barrier by mechanical injury activates TGF-β1, leading to LM-332 expression. Together, our data suggest a novel mechanism for triggering the production of LM-332 after epithelial injury.

Concentration-dependent effect of fumonisin B1 on apoptosis in oesophageal cancer cells

2017 ◽  
Vol 37 (7) ◽  
pp. 762-771 ◽  
Author(s):  
RB Khan ◽  
A Phulukdaree ◽  
AA Chuturgoon
Keyword(s):  
Cell Viability ◽  
Oesophageal Cancer ◽  
Caspase 3 ◽  
Quantitative Polymerase Chain Reaction ◽  
Fumonisin B1 ◽  
Annexin V ◽  
Tail Length ◽  
Bax Protein ◽  
Genotoxic Carcinogens ◽  
Parp 1

The geographical distribution of oesophageal cancer is linked to the exposure of fumonisin B1 (FB1), a mycotoxin produced by fungi that contaminates staple food worldwide. Non-genotoxic carcinogens like FB1 disturb homeostasis through increased cell proliferation or suppression of apoptosis. This study investigated the involvement of FB1 (0–20 μM) in spindle-shaped N-cadherin (+) CD45 (−) osteoblastic (SNO) cell death. Cell viability and death were assessed using the MTS and Annexin V-Fluos assays, respectively. Caspase activities were determined luminometrically and the comet assay assessed DNA damage. Induction of oxoguanine glycosylase 1 (OGG1) was measured using quantitative Polymerase Chain Reaction (qPCR), while cleaved poly (ADP-ribose) polymerase 1 (PARP-1) and Bax were determined by western blotting. Cell viability and PARP-1 cleavage were not affected by 1.25 μM FB1, but phosphatidylserine externalization, Bax protein expression, caspase activity, comet tail length and OGG1 transcripts were increased. The reduced cell viability in 10 μM FB1-treated cells was accompanied by corresponding increases in externalized phosphatidylserine, Bax, caspase-3/7 activity and cleaved PARP-1. The OGG1 transcripts were not significantly increased, but comet tails were increased. Bax, caspase-3/7 activities and cleaved PARP-1 were inhibited at 20 μM FB1. In addition, the OGG1 transcript levels were decreased ( p < 0.0001) along with comet lengths ( p < 0.0001). This study showed that FB1-induced apoptosis in SNO cells may be caspase-dependent or caspase-independent; the pathway used depends on the exposure concentration.

scholarly journals Transforming growth factor-β1 up-regulates connexin43 expression in osteocytes via canonical Smad-dependent signaling pathway

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Wenjing Liu ◽  
Yujia Cui ◽  
Jianxun Sun ◽  
Linyi Cai ◽  
Jing Xie ◽  
...  
Keyword(s):  
Growth Factor ◽  
Connexin 43 ◽  
Transforming Growth Factor ◽  
Bone Cells ◽  
Underlying Mechanism ◽  
Transforming Growth Factor Β1 ◽  
Type I ◽  
Gap Junctional Intercellular Communication ◽  
Cx43 Expression ◽  
Tgf Β1

Connexin 43 (Cx43)-mediated gap junctional intercellular communication (GJIC) has been shown to be important in regulating multiple functions of bone cells. Transforming growth factor-β1 (TGF-β1) exhibited controversial effects on the expression of Cx43 in different cell types. To date, the effect of TGF-β1 on the Cx43 expression of osteocytes is still unknown. In the present study, we detected the expression of TGF-β1 in osteocytes and bone tissue, and then used recombinant mouse TGF-β1 to elucidate its effect on gap junctions (GJs) of osteocytes. Our data indicated that TGF-β1 up-regulated both mRNA and protein expression of Cx43 in osteocytes. Together with down-regulation of Cx43 expression after being treated with TGF-β type I receptor inhibitor Repsox, we deduced that TGF-β1 can positively regulate Cx43 expression in osteocytes. Thus we next focussed on the downstream signals of TGF-β and found that TGF-β1-mediated smads, Smad3 and Smad4, to translocate into nucleus. These translocated signal proteins bind to the promoter of Gja1 which was responsible for the changed expression of Cx43. The present study provides evidence that TGF-β1 can enhance GJIC between osteocytes through up-regulating Cx43 expression and the underlying mechanism involved in the activation of Smad-dependent pathway.

Abstract 17285: A Selective Transforming Growth Factor-β and Growth Differentiation Factor-15 Ligand Trap Attenuates Pulmonary Hypertension

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Lai-Ming Yung ◽  
Samuel D Paskin-Flerlage ◽  
Ivana Nikolic ◽  
Scott Pearsall ◽  
Ravindra Kumar ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Rna Seq ◽  
Differentiation Factor ◽  
Group I ◽  
Tgf Β1

Introduction: Excessive Transforming Growth Factor-β (TGF-β) signaling has been implicated in pulmonary arterial hypertension (PAH), based on activation of TGF-β effectors and transcriptional targets in affected lungs and the ability of TGF-β type I receptor (ALK5) inhibitors to improve experimental PAH. However, clinical use of ALK5 inhibitors has been limited by cardiovascular toxicity. Hypothesis: We tested whether or not selective blockade of TGF-β and Growth Differentiation Factor (GDF) ligands using a recombinant TGFβ type II receptor extracellular domain Fc fusion protein (TGFBRII-Fc) could impact experimental PAH. Methods: Male SD rats were injected with monocrotaline (MCT) and received vehicle or TGFBRII-Fc (15 mg/kg, twice per week, i.p.). C57BL/6 mice were treated with SU-5416 and hypoxia (SUGEN-HX) and received vehicle or TGFBRII-Fc. RNA-Seq was used to profile transcriptional changes in lungs of MCT rats. Circulating levels of GDF-15 were measured in 241 PAH patients and 41 healthy controls. Human pulmonary artery smooth muscle cells were used to examine signaling in vitro . Results: TGFBRII-Fc is a selective ligand trap, inhibiting the ability of GDF-15, TGF-β1, TGF-β3, but not TGF-β2 to activate SMAD2/3 in vitro . In MCT rats, prophylactic treatment with TGFBRII-Fc normalized expression of TGF-β transcriptional target PAI-1, attenuated PAH and vascular remodeling. Delayed administration of TGFBRII-Fc in rats with established PAH at 2.5 weeks led to improved survival, decreased PAH and remodeling at 5 weeks. Similar findings were observed in SUGEN-HX mice. No valvular abnormalities were found with TGFBRII-Fc treatment. RNA-Seq revealed GDF-15 to be the most highly upregulated TGF-β ligand in the lungs of MCT rats, with only modest increases in TGF-β1 and no change in TGF-β2/3 observed, suggesting a dominant role of GDF-15 in the pathophysiology of this model. Plasma levels of GDF-15 were significantly increased in patients with diverse etiologies of WHO Group I PAH. Conclusions: These findings demonstrate that a selective TGF-β/GDF-15 trap attenuates experimental PAH, remodeling and mortality, without causing valvulopathy. These data highlight the potential role of GDF-15 as a pathogenic molecule and therapeutic target in PAH.

scholarly journals Metformin and Inhibition of Transforming Growth Factor-Beta Stimulate In Vitro Transport in Primary Renal Tubule Cells

2020 ◽  
Vol 26 (19-20) ◽  
pp. 1091-1098
Author(s):  
Harold Love ◽  
Rachel Evans ◽  
Harvey David Humes ◽  
Shuvo Roy ◽  
Roy Zent ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Renal Tubule ◽  
Growth Factor Beta ◽  
Tubule Cells

scholarly journals Vascular endothelial growth factor-C: its unrevealed role in fibrogenesis

2014 ◽  
Vol 306 (6) ◽  
pp. H789-H796 ◽  
Author(s):  
Tieqiang Zhao ◽  
Wenyuan Zhao ◽  
Weixin Meng ◽  
Chang Liu ◽  
Yuanjian Chen ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Type I ◽  
Vascular Endothelial ◽  
Factor C ◽  
Endothelial Growth Factor ◽  
Tgf Β1

Vascular endothelial growth factor (VEGF)-C is a key mediator of lymphangiogenesis. Our recent study shows that VEGF-C/VEGF receptors (VEGFR)-3 are significantly increased in the infarcted rat myocardium, where VEGFR-3 is expressed not only in lymph ducts but also in myofibroblasts, indicating that VEGF-C has an unrevealed role in fibrogenesis during cardiac repair. The current study is to explore the regulation and molecular mechanisms of VEGF-C in fibrogenesis. The potential regulation of VEGF-C on myofibroblast differentiation/growth/migration, collagen degradation/synthesis, and transforming growth factor (TGF)-β and ERK pathways was detected in cultured cardiac myofibroblasts. Our results showed that VEGF-C significantly increased myofibroblast proliferation, migration, and type I/III collagen production. Matrix metalloproteinase (MMP)-2 and -9 were significantly elevated in the medium of VEGF-C-treated cells, coincident with increased tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Furthermore, VEGF-C activated the TGF-β1 pathway and ERK phosphorylation, which was significantly suppressed by TGF-β or ERK blockade. This is the first study indicating that in addition to lymphangiogenesis, VEGF-C is also involved in fibrogenesis through stimulation of myofibroblast proliferation, migration, and collagen synthesis, via activation of the TGF-β1 and ERK pathways.

scholarly journals Smad7 Abrogates Transforming Growth Factor-β1-mediated Growth Inhibition in COLO-357 Cells through Functional Inactivation of the Retinoblastoma Protein

2005 ◽  
Vol 280 (23) ◽  
pp. 21858-21866 ◽  
Author(s):  
Nichole Boyer Arnold ◽  
Murray Korc
Keyword(s):  
Growth Factor ◽  
Growth Inhibition ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Retinoblastoma Protein ◽  
Transforming Growth Factor Β1 ◽  
Type I ◽  
Pancreatic Cancer Cells ◽  
Induced Apoptosis ◽  
Tgf Β1

Smad7 is overexpressed in 50% of human pancreatic cancers. COLO-357 pancreatic cancer cells engineered to overexpress Smad7 are resistant to the actions of transforming growth factor-β1 (TGF-β1) with respect to growth inhibition and cisplatin-induced apoptosis but not with respect to modulation of gene expression. To delineate the mechanisms underlying these divergent consequences of Smad7 overexpression, we studied the effects of Smad7 on TGF-β1-dependent signaling pathways and cell cycle regulating proteins. TGF-β1 induced the phosphorylation of MAPK, p38 MAPK, and AKT2 irrespective of the levels of Smad7, and inhibitors of these pathways did not alter TGF-β1 actions on cell growth. By contrast, Smad7 overexpression interfered with TGF-β1-mediated attenuation of cyclin A and B levels, inhibition of cdc2 dephosphorylation and CDK2 inactivation, up-regulation of p27, and the maintenance of the retinoblastoma protein (RB) in a hypophosphorylated state. Smad7 also suppressed TGF-β1-mediated inhibition of E2F activity but did not alter TGF-β1-mediated phosphorylation of Smad2, the nuclear translocation of Smad2/3/4, or DNA binding of the Smad2/3/4 complex. Although Smad7 did not associate with the type I TGF-β receptor (TβRI), SB-431542, an inhibitor of the kinase activity of this receptor, blocked TGF-β1-mediated effects on Smad-2 phosphorylation. These findings point toward a novel paradigm whereby Smad7 acts to functionally inactivate RB and de-repress E2F without blocking the activation of TβRI and the nuclear translocation of Smad2/3, thereby allowing for TGF-β1 to exert effects in a cancer cell that is resistant to TGF-β1-mediated growth inhibition.

Significance of Increased Accumulation of Type VI Collagen and Transforming Growth Factor βi in Tubulointerstitial Damage in Hypertensive Nephrosclerosis: An Immunohistochemical Study

1996 ◽  
Vol 24 (2) ◽  
pp. 199-208 ◽  
Author(s):  
M S Razzaque ◽  
T Harada ◽  
T Taguchi
Keyword(s):  
Growth Factor ◽  
Basement Membrane ◽  
Glomerular Basement Membrane ◽  
Transforming Growth Factor ◽  
Tubulointerstitial Injury ◽  
Tubular Basement Membrane ◽  
Type Vi Collagen ◽  
Hypertensive Nephrosclerosis ◽  
Tubulointerstitial Damage ◽  
Tgf Β1

The distribution of type VI collagen and transforming growth factor β1 (TGF β1) was studied by immunohistochemistry in 12 renal biopsy specimens of hypertensive nephrosclerosis and five control cases. In control kidneys, the immunostaining of type VI collagen was found in the mesangium, glomerular basement membrane and tubular basement membrane. For TGF β, mesangium, glomerular basement membrane, tubular basement membrane and tubular epithelial cells stained positively in the control kidneys. In contrast to the control cases, markedly increased immunostaining for both type VI collagen and TGF β1 was consistently observed in tubulointerstitial damage in hypertensive nephrosclerosis. These immunohistochemical findings provide the evidence for a parallel increase of both type VI collagen and TGF β1 during the process of tubulointerstitial injury in hypertensive nephrosclerosis. From the results of the present study, it is speculated that TGF β1 may contribute to the tubulointerstitial injury by stimulating increased synthesis of various extracellular matrix including type VI collagen.

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