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.

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.

scholarly journals C-peptide prevents SMAD3 binding to alpha promoters to inhibit collagen type IV synthesis

2018 ◽  
Vol 61 (1) ◽  
pp. 47-56 ◽  
Author(s):  
Yanning Li ◽  
Yan Zhong ◽  
Wenjian Gong ◽  
Xuehan Gao ◽  
Huanli Qi ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Protein Content ◽  
Collagen Type ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Mesangial Cells ◽  
Collagen Type Iv ◽  
Pathological Changes ◽  
C Peptide ◽  
Type Iv

Activation of transforming growth factor β1 (TGFB1)/SMAD3 signaling may lead to additional synthesis of collagen type IV (COL4), which is a major contributor to extracellular matrix (ECM) accumulation in diabetic nephropathy (DN). C-peptide can attenuate fibrosis to have unique beneficial effects in DN. However, whether and how C-peptide affects TGFB1/SMAD3-activated COL4 synthesis is unclear. In this study, pathological changes, expression of COL4 a1-a5 chains (Col4a1-a5), COL4 distribution and protein and TGFB1 and SMAD3 protein were first assessed in a rat model of diabetes. Then, rat mesangial cells were treated with high glucose (HG) and/or C-peptide to investigate the underlying mechanism.Col4a1-a5expression, COL4 protein and secretion, TGFB1 protein, SMAD3 nuclear translocation and binding of SMAD3 to its cognate sites in the promoters ofCol4a1a2,Col4a3a4andCol4a5were measured. It was found that C-peptide attenuated glomerular pathological changes and suppressed renalCol4a1-a5mRNA expression, COL4 protein content and TGFB1 protein content. C-peptide had a dose-dependent effect to inhibitCol4a1-a5mRNA expression, COL4 protein content and secretion, in HG-stimulated mesangial cells. In addition, the HG-induced increase in TGFB1 protein content was significantly reduced by C-peptide. Although not apparently affecting SMAD3 nuclear translocation, C-peptide prevented SMAD3 from binding to its sites in theCol4a1a2,Col4a3a4andCol4a5promoters in HG-stimulated mesangial cells. In conclusion, C-peptide could prevent SMAD3 from binding to its sites in theCol4a1a2,Col4a3a4andCol4a5promoters, to inhibit COL4 generation. These results may provide a mechanism for the alleviation of fibrosis in DN by C-peptide.

scholarly journals Liraglutide suppresses production of extracellular matrix proteins and ameliorates renal injury of diabetic nephropathy by enhancing Wnt/β-catenin signaling

2020 ◽  
Vol 319 (3) ◽  
pp. F458-F468 ◽  
Author(s):  
Linjing Huang ◽  
Tingting Lin ◽  
Meizhen Shi ◽  
Xiuqing Chen ◽  
Peiwen Wu
Keyword(s):  
Diabetic Nephropathy ◽  
Collagen Type ◽  
Mesangial Cells ◽  
Smooth Muscle Actin ◽  
Diabetic Rats ◽  
Collagen Type Iv ◽  
Signaling Proteins ◽  
Muscle Actin ◽  
Type Iv

The Wnt/β-catenin signaling pathway is involved in production of the extracellular matrix (ECM) by mesangial cells (MCs). Recent studies by us and others have demonstrated that glucagon-like peptide-1 receptor agonists (GLP-1RAs) have protective effects against diabetic nephropathy. The purpose of the present study was to investigate whether the Wnt/β-catenin signaling in MCs contributes to GLP-1RA-induced inhibition of ECM accumulation and mitigation of glomerular injury in diabetic nephropathy. In cultured human mesangial cells, liraglutide (a GLP-1RA) treatment significantly reduced high glucose (HG)-stimulated production of fibronectin, collagen type IV, and α-smooth muscle actin, and the liraglutide effects were significantly attenuated by XAV-939, a selective inhibitor of Wnt/β-catenin signaling. Furthermore, HG treatment significantly decreased protein abundance of Wnt4, Wnt5a, phospho-glycogen synthase kinase-3β, and β-catenin. These HG effects on Wnt/β-catenin signaling proteins were significantly blunted by liraglutide treatment. For in vivo experiments, we administered liraglutide (200 μg·kg−1·12 h−1) by subcutaneous injection to streptozocin-induced type 1 diabetic rats for 8 wk. Administration of liraglutide significantly improved elevated blood urine nitrogen, serum creatinine, and urinary albumin excretion rate and alleviated renal hypertrophy, mesangial expansion, and glomerular fibrosis in type 1 diabetic rats, whereas blood glucose level and body weight did not have significant changes. Consistent with the in vitro experiments, liraglutide treatment significantly reduced the diabetes-induced increases in glomerular fibronectin, collagen type IV, and α-smooth muscle actin and decreases in glomerular Wnt/β-catenin signaling proteins. These results suggest that liraglutide alleviated glomerular ECM accumulation and renal injury in diabetic nephropathy by enhancing Wnt/β-catenin signaling.

Mechanism of saikosaponin-d in the regulation of rat mesangial cell proliferation and synthesis of extracellular matrix proteinsThis paper is one of a selection of papers in this Special Issue, entitled International Symposium on Recent Advances in Molecular, Clinical, and Social Medicine, and has undergone the Journal's usual peer-review process.

2007 ◽  
Vol 85 (2) ◽  
pp. 169-174 ◽  
Author(s):  
Ning Zu ◽  
Ping Li ◽  
Ning Li ◽  
Patrick Choy ◽  
Yuewen Gong
Keyword(s):  
Extracellular Matrix ◽  
Cell Proliferation ◽  
Type Iv Collagen ◽  
Mesangial Cells ◽  
Kidney Diseases ◽  
Peer Review Process ◽  
Matrix Proteins ◽  
Glomerular Mesangial Cells ◽  
Type Iv ◽  
Tgf Β1

Glomerulosclerosis is a common disorder in many types of chronic kidney diseases. Previous studies have shown that glomerular mesangial cells (MCs) play an important role in the pathogenesis of glomerulosclerosis. The ability of saikosaponin-d (SSd) to reduce the damage of kidney in progressive glomerulosclerosis has been demonstrated. In this study, the effects of saikosaponin-d on MC proliferation and synthesis of extracellular matrix proteins were investigated. Rat MCs were isolated from Wistar rats and cultured in Dulbecco's modified Eagle's medium. MCs were challenged with lipopolysacchorides and incubated with different concentrations of SSd. Cell proliferation and cytotoxicity were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, and lactate dehydrogenase assays. Type IV collagen, fibronectin, and TGF-β1 in the conditioned medium were measured. The expression of cyclin-dependent kinase 4, c-Jun, and c-Fos was determined by immunohistochemistry. At a concentration of 4 µg/mL or lower, SSd inhibited MC proliferation but did not cause cell death. SSd also inhibited lipopolysaccharide-induced secretion of type IV collagen, fibronectin, and TGF-β1 in MCs. Additionally, SSd reduced the expression of CDK4, c-Jun, and c-Fos in MCs. We conclude that SSd inhibited MC proliferation and synthesis of extracullular matrix proteins through the downregulation of the CDK4, c-Jun, and c-Fos genes.

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.

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