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.

The Effect of Nifedipine (NIF) on [3H]-Cyclosporin a (CYA) Uptake Into Human Proximal Tubular Cells (PTC)

1990 ◽  
Vol 78 (s22) ◽  
pp. 34P-34P
Author(s):  
PG McNally ◽  
T Horsburgh ◽  
J Walls ◽  
J Feehally
Keyword(s):  
Cyclosporin A ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular

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.

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 Advanced Glycated End-Products Affect HIF-Transcriptional Activity in Renal Cells

2013 ◽  
Vol 27 (11) ◽  
pp. 1918-1933 ◽  
Author(s):  
Tzvetanka Bondeva ◽  
Juliane Heinzig ◽  
Carola Ruhe ◽  
Gunter Wolf
Keyword(s):  
Transcriptional Activation ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Mesangial Cells ◽  
Hypoxia Inducible Factor ◽  
Mrna Levels ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
End Products ◽  
Proximal Tubular

Advanced glycated end-products (AGEs) are ligands of the receptor for AGEs and increase in diabetic disease. MAPK organizer 1 (Morg1) via its binding partner prolyl-hydroxylase domain (PHD)-3 presumably plays a role in the regulation of hypoxia-inducible factor (HIF)-1α and HIF-2α transcriptional activation. The purpose of this study was to analyze the influence of AGEs on Morg1 expression and its correlation to PHD3 activity and HIF-transcriptional activity in various renal cell types. The addition of glycated BSA (AGE-BSA) significantly up-regulated Morg1 mRNA levels in murine mesangial cells and down-regulated it in murine proximal tubular cells and differentiated podocytes. These effects were reversible when the cells were preincubated with a receptor for α-AGE antibody. AGE-BSA treatment induced a relocalization of the Morg1 cellular distribution compared with nonglycated control-BSA. Analysis of PHD3 activity demonstrated an elevated PHD3 enzymatic activity in murine mesangial cells but an inhibition in murine proximal tubular cells and podocytes after the addition of AGE-BSA. HIF-transcriptional activity was also affected by AGE-BSA treatment. Reporter gene assays and EMSAs showed that AGEs regulate HIF- transcriptional activity under nonhypoxic conditions in a cell type-specific manner. In proximal tubular cells, AGE-BSA stimulation elevated mainly HIF-1α transcriptional activity and to a lesser extent HIF-2α. We also detected an increased expression of the HIF-1α and the HIF-2α proteins in kidneys from Morg1 heterozygous (HZ) placebo mice compared with the Morg1 wild-type (WT) placebo-treated mice, and the HIF-1α protein expression in the Morg1 HZ streptozotocin-treated mice was significantly higher than the WT streptozotocin-treated mice. Analysis of isolated mesangial cells from Morg1 HZ (±) and WT mice showed an inhibited PHD3 activity and an increased HIF-transcriptional activity in cells with only one Morg1 allele. These findings are important for a better understanding of the molecular mechanisms of diabetic nephropathy.

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.

Cyclosporin A stimulates apical Na+/H+ exchange in LLC-PK1/PKE20 proximal tubular cells

2006 ◽  
Vol 21 (7) ◽  
pp. 939-946 ◽  
Author(s):  
Thomas Epting ◽  
Kathrin Hartmann ◽  
Anna Sandqvist ◽  
Roland Nitschke ◽  
Nader Gordjani
Keyword(s):  
Cyclosporin A ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular

Cellular Basis of Aminoglycoside Nephrotoxicity

Physiology ◽  
1989 ◽  
Vol 4 (5) ◽  
pp. 181-184
Author(s):  
R Hori ◽  
K-i Inui
Keyword(s):  
Clinical Problem ◽  
Aminoglycoside Antibiotics ◽  
Transport Mechanisms ◽  
Renal Cells ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Cellular Basis ◽  
Important Clinical Problem ◽  
Proximal Tubular

Nephrotoxicity, produced by aminoglycoside antibiotics, is now being studied in a useful model of cultured renal cells. These studies could provide new insights into an important clinical problem by disclosing the transport mechanisms of aminoglycoside into the proximal tubular cells and the cellular characteristics of nephrotoxicity.

Sign in / Sign up

Export Citation Format

Share Document