BMP7 antagonizes TGF-β-dependent fibrogenesis in mesangial cells

2003 ◽  
Vol 284 (5) ◽  
pp. F1006-F1013 ◽  
Author(s):  
Shinong Wang ◽  
Raimund Hirschberg
Keyword(s):  
Growth Factor ◽  
Collagen Type ◽  
Mesangial Cells ◽  
Tissue Growth ◽  
Luciferase Reporter ◽  
Renal Diseases ◽  
Collagen Type Iv ◽  
Mrna Levels ◽  
Type Iv ◽  
Pai 1

Exogenous administration of recombinant human bone morphogenetic protein (BMP)-7 was recently shown to ameliorate renal glomerular and interstitial fibrosis in rodents with experimental renal diseases. We tested the hypothesis that BMP7 functions by antagonizing profibrogenic events that are induced by transforming growth factor (TGF)-β in cultured mesangial cells. Incubation of murine mesangial cells with TGF-β (50–200 pM) increased cell-associated collagen type IV and fibronectin, soluble collagen type IV, thrombospondin, and connective tissue growth factor (CTGF). Coincubation with recombinant human BMP7 (200 pM) reduced the increase of these ECM proteins and CTGF. The changes in collagen type IV and fibronectin proteins occurred without concomitant changes in collagen type α1IV and fibronectin mRNA levels, suggesting that TGF-β and BMP7 act primarily by affecting ECM protein degradation. Indeed, TGF-β decreases the levels and activity of matrix metalloprotease (MMP)-2, the major metalloprotease that is secreted by mesangial cells. Moreover, BMP7 inhibits TGF-β-induced activation of MMP2. Because TGF-β reduces the activity of MMPs through increasing plasminogen activator inhibitor (PAI)-1, we tested whether BMP7 interferes with this TGF-β effect. BMP7 reduces, by about two-thirds, the activation of a PAI-1 promoter/luciferase reporter in cells stably transfected with this construct. The findings from these studies indicate that BMP7 reduces TGF-β-induced ECM protein accumulation in cultured mesangial cells primarily by maintaining levels and activity of MMP2 partially through prevention of TGF-β-dependent upregulation of PAI-1.

Effect of Simvastatin on Expression of Transforming Growth Factor-β and Collagen Type IV in Rat Mesangial Cells

Pharmacology ◽  
2011 ◽  
Vol 88 (3-4) ◽  
pp. 188-192 ◽  
Author(s):  
Yan-Bo Li ◽  
Jia-Jing Yin ◽  
Hong-Jie Wang ◽  
Jun Wang ◽  
Hui Tian ◽  
...  
Keyword(s):  
Growth Factor ◽  
Collagen Type ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Transforming Growth Factor Β ◽  
Collagen Type Iv ◽  
Type Iv

Glycated albumin stimulation of PKC-β activity is linked to increased collagen IV in mesangial cells

1999 ◽  
Vol 276 (5) ◽  
pp. F684-F690 ◽  
Author(s):  
Margo P. Cohen ◽  
Fuad N. Ziyadeh ◽  
Gregory T. Lautenslager ◽  
Jonathan A. Cohen ◽  
Clyde W. Shearman
Keyword(s):  
Collagen Type ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Glycated Albumin ◽  
Matrix Proteins ◽  
Collagen Type Iv ◽  
Type Iv ◽  
Pkc Β ◽  
Tgf Β1 ◽  
Stimulation Of

Albumin modified by Amadori-glucose adducts induces coordinate increases in the expression of extracellular matrix proteins, transforming growth factor (TGF)-β1, and the TGF-β type II receptor in glomerular mesangial cells. Because activation of protein kinase C (PKC) accompanies the increased mesangial cell expression of matrix proteins and TGF-β1 induced by high ambient glucose, we postulated that glycated albumin (GA) modulates PKC activity and that PKC participates in mediating the GA-induced stimulation of matrix production. To test this hypothesis, we examined the effects of PKC inhibitors on collagen type IV production by mouse or rat mesangial cells incubated with GA, and the influence of GA on PKC activity in these cells. Increased collagen type IV production evoked by GA in 5.5 and 25 mM glucose in mouse mesangial cells was prevented by both general (GF-109203X) and β-specific (LY-379196) PKC inhibitors. Total PKC activity, measured by phosphorylation of a PKC-specific substrate, increased with time after exposure of rat mesangial cells to GA compared with the nonglycated, glucose-free counterpart. GA caused an increase in PKC-β1 membrane-bound fraction and in total PKC activity in media containing physiological (5.5 mM) glucose concentrations in rat mesangial cells, confirming that the glucose-modified protein, and not a “hyperglycemic” milieu, was responsible. The findings indicate that Amadori-modified albumin stimulates mesangial cell PKC activity, and that activation of the PKC-β isoform is linked to the stimulation of collagen type IV production.

Effect of everolimus on angiogenic biomarkers in patients with tuberous sclerosis complex (TSC): Results from EXIST-1 and EXIST-2.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10619-10619
Author(s):  
David Neal Franz ◽  
Christopher Kingswood ◽  
Sergiusz Jozwiak ◽  
Klemens Budde ◽  
Elena Belousova ◽  
...  
Keyword(s):  
Growth Factor ◽  
Collagen Type ◽  
Plasma Concentrations ◽  
Collagen Type Iv ◽  
Subependymal Giant Cell Astrocytoma ◽  
Renal Angiomyolipoma ◽  
Vegf Receptor ◽  
Double Blind ◽  
Type Iv

10619 Background: The efficacy and safety of everolimus, an oral mTOR inhibitor, was assessed in two randomized, double-blind, placebo-controlled, phase 3 trials: EXIST-1 (NCT00789828) and EXIST-2 (NCT00790400). EXIST-1 examined everolimus for the treatment of subependymal giant cell astrocytoma (SEGA) associated with TSC and EXIST-2 for the treatment of renal angiomyolipoma (AML) associated with either TSC or sporadic lymphangioleiomyomatosis. In each instance, everolimus was superior to placebo for the primary endpoints, SEGA and renal AML response rates. Inhibitors of mTOR have antiangiogenic effects on tumor growth in vitro and in vivo. Methods: Patients were randomized to receive everolimus (n=78) starting at 4.5 mg/m2/day (target trough, 5-15 ng/mL) or placebo (n=39) in EXIST-1 and 10 mg/day everolimus (n=79) or placebo (n=39) in EXIST-2. Plasma samples were taken at baseline and pre-dosing on day 1 of weeks 4, 12, 24, 36, and 48 of treatment. Angiogenic markers of interest were vascular endothelial growth factor (VEGF)-A and -D, placental growth factor (PlGF), soluble VEGF receptor-1 (sVEGFR1), soluble VEGF receptor 2 (sVEGFR2), c-Kit, and collagen type IV. Results: Compared with placebo, a sustained ~30% and ~60% increase in VEGF-A was observed in the everolimus arm of EXIST-1 and EXIST-2, respectively. A concomitant decrease in collagen type IV (~25% EXIST-1; ~45% EXIST-2) and sVEGFR2 (~25% both trials) was also observed in the everolimus arm. A sustained decrease (~60%) in VEGF-D was observed in the everolimus arm of EXIST-2, but not EXIST-1. In both studies, no change was observed in PlGF, sVEGFR1, or c-Kit plasma concentrations in the everolimus arm or any biomarkers evaluated in the placebo arm. Baseline sVEGFR2 and VEGF-D were ~40% and ~4-fold higher, respectively, while VEGF-A was ~50% lower in EXIST-2 compared with EXIST-1. A similar baseline plasma concentration for the other biomarkers was noted in both studies. Conclusions: Patients presenting with SEGA or renal AML associated with TSC had a reduction in plasma concentrations of sVEGFR2, collagen type IV, and VEGF-D (AML only) and an increase in VEGF-A. Everolimus may have antiangiogenic properties in TSC patients.

scholarly journals miR-29c induction contributes to downregulation of vascular extracellular matrix proteins by glucocorticoids

2015 ◽  
Vol 309 (2) ◽  
pp. C117-C125 ◽  
Author(s):  
Tsai-Der Chuang ◽  
William J. Pearce ◽  
Omid Khorram
Keyword(s):  
Collagen Type ◽  
Rat Aorta ◽  
Matrix Metalloproteinase 2 ◽  
Luciferase Reporter ◽  
Collagen Type Iv ◽  
Loss Of Function ◽  
Protein Levels ◽  
Maternal Undernutrition ◽  
Type Iv ◽  
Negative Controls

Maternal undernutrition increases maternal glucocorticoids (GCs) and alters microRNA expression in offspring. Given that the mechanisms of GC action on vascular development are not clear, this study examined the influence of GCs on microRNA 29c (miR-29c) and its predicted targets in primary rat aorta smooth muscle cells (RAOSMCs). Dexamethasone (Dex) and corticosterone (Cor) time-dependently increased miR-29c expression and reduced collagen type III (Col3A1), collagen type IV (Col4A5), elastin (ELN), and matrix metalloproteinase-2 (MMP2) protein in RAOSMCs. These effects were blocked by mifepristone. These genes were also targeted by miR-29c, as confirmed by a significant decrease in luciferase reporter activity of Col3A1 (34%), Col4A5 (45%), ELN (17%), and MMP2 (28%). In cells transfected with reporter plasmids, including the 3′-untranslated region of genes targeted by miR-29c, treatment with Dex or Cor also resulted in decreases in luciferase activity. Gain or loss of function of miR-29c significantly altered mRNA expression of Col3A1 (26% and 26%, respectively), Col4A5 (28% and 32%, respectively), and MMP2 (24% and 14%, respectively) but did not affect ELN. Gain or loss of function of miR-29c also significantly altered protein levels of Col3A1 (51% and 16%, respectively), Col4A5 (56% and 22%, respectively), ELN (53% and 71%, respectively), and MMP2 (28% and 53%, respectively). Coincubation of anti-miR-29c with Dex or Cor partially attenuated the effects of these steroids on protein expression of Col3A1 (25% and 24%, respectively), Col4A5 (26% and 44%, respectively), ELN (31% and 55%, respectively), and MMP2 (46% and 26%, respectively) in RAOSMCs compared with anti-miR negative controls. Our results demonstrate that GCs regulate the expression of Col3A1, Col4A5, ELN, and MMP2, at least in part, through induction of miR-29c.

Mechanisms through which bradykinin promotes glomerular injury in diabetes

2005 ◽  
Vol 288 (3) ◽  
pp. F483-F492 ◽  
Author(s):  
Yan Tan ◽  
Bing Wang ◽  
Joo-Seob Keum ◽  
Ayad A. Jaffa
Keyword(s):  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Tissue Growth ◽  
Collagen I ◽  
Mrna Levels ◽  
Glomerular Injury ◽  
Western Blots ◽  
Protein Levels

In diabetes, mesangial cell proliferation and extracellular matrix expansion are critical components in the development of glomerulosclerosis. We reported that diabetes alters the activity of the kallikrein-kinin system and that these alterations contribute to the development of diabetic nephropathy. The present study examined the influence of streptozotocin-induced diabetes on the renal expression of bradykinin (BK) B2 receptors (B2KR), connective tissue growth factor (CTGF), transforming growth factor-β (TGF-β), and TGF-β type II receptor (TGF-βRII) and assessed the signaling mechanisms through which B2KR activation may promote glomerular injury. Eight weeks after the induction of diabetes, renal mRNA levels of B2KR, CTGF, and TGF-β as well as protein levels of CTGF and TGF-βRII were measured in control (C), diabetic (D), and insulin-treated diabetic (D+I) rats. Renal B2KR and TGF-β mRNA levels expressed relative to β-actin mRNA levels and CTGF and TGF-βRII protein levels were significantly increased in D and D+I rats compared with C rats ( P < 0.03, n = 5). To assess the contribution of B2KR activation on modulating the expression of CTGF, TGF-βRII, and collagen I, mesangial cells (MC) were treated with BK (10−8 M) for 24 h and CTGF and TGF-βRII protein levels were measured by Western blots and collagen I mRNA levels were measured by RT-PCR. A two- to threefold increase in CTGF and TGF-βRII protein levels was observed in response to BK stimulation ( P < 0.001, n = 6). In addition, a marked increase in collagen I mRNA levels was observed in response to BK stimulation. Treatment of MC with BK (10−8 M) for 5 min significantly increased the tyrosine phosphorylation of p60src kinase and of p42/p44 MAPK ( P < 0.05, n = 4). Inhibition of src kinase by PP1 (10 μM) inhibited the increase in p42/p44 MAPK activation in response to BK. Finally, to determine whether BK stimulates CTGF, TGF-βRII, and collagen I expression via activation of MAPK pathways, MC were pretreated with an inhibitor of p42/p44 MAPK (PD-98059) for 45 min, followed by BK (10−8 M) stimulation for 24 h. Selective inhibition of p42/p44 MAPK significantly inhibited the BK-induced increase in CTGF, TGF-βRII, and collagen I levels. These findings are the first to demonstrate that BK regulates the expression of CTGF, TGF-βRII, and collagen I in MC and provide a mechanistic pathway through which B2KR activation may contribute to the development of diabetic nephropathy.

scholarly journals Expression of beta 1-integrins on activated mesangial cells in human glomerulonephritis.

1997 ◽  
Vol 8 (11) ◽  
pp. 1679-1687 ◽  
Author(s):  
T Kuhara ◽  
S Kagami ◽  
Y Kuroda
Keyword(s):  
Collagen Type ◽  
Mesangial Cells ◽  
Critical Role ◽  
Laminin Receptor ◽  
Collagen Type Iv ◽  
Tgf Beta ◽  
Fibronectin Receptor ◽  
Glomerular Cell ◽  
Matrix Deposition ◽  
Type Iv

beta 1-integrins, a family of cell-surface receptors, mediate cell-matrix interactions that play a critical role in tissue development and tissue remodeling after injury. In this study, to clarify the importance of beta 1-integrins in human glomerulonephritis (GN), the relationship among the glomerular expression of beta 1-integrins, their ligand matrix components, alpha-smooth muscle actin (alpha-SM actin) as a marker of activated mesangial cells (MC), transforming growth factor-beta (TGF-beta), and glomerular cellularity in two normal kidneys, ten minimal change nephrotic syndrome, 23 immunoglobulin A (IgA) GN, 13 lupus GN, and four membranous GN kidneys were studied. Immunostaining was performed on frozen sections, using monoclonal anti-alpha-SM actin antibody and polyclonal antibodies against fibronectin, collagen type IV, laminin, each subunit of alpha 1 beta 1 (collagen/laminin receptor), alpha 5 beta 1 (fibronectin receptor) and TGF-beta. Quantitation of staining indicated that the glomerular expression of alpha 1 beta 1 and alpha 5 beta 1 integrins correlated with the mesangial amounts of their ligands, collagen type IV, laminin and fibronectin (P < 0.01), alpha-SM actin (P < 0.01), and TGF-beta (P < 0.01). In addition, a correlation was observed between an increased expression of alpha 1 beta 1 and alpha 5 beta 1 integrins and the degree of glomerular cell proliferation (P < 0.01). Double immunostaining showed that activated MC expressing alpha-SM actin strongly expressed alpha 1 beta 1 and alpha 5 beta 1 integrins, and these MC phenotypic alterations paralleled the level of glomerular TGF-beta staining (P < 0.01). In conclusion, enhanced expression of beta 1-integrins by activated MC may contribute to the pathological mesangial remodeling characterized by MC proliferation and matrix deposition in human GN. Increased glomerular TGF-beta appears to be involved in these MC phenotypic changes.

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