12 results on '"Iglesias DE"'
Search Results
2. Inhibiting albumin glycation in vivo ameliorates glomerular overexpression of TGF-β1
- Author
-
Cohen, Margo P, Ziyadeh, Fuad N, Hong, Soon Won, Shearman, Clyde W, Hud, Elizabeth, Lautenslager, Gregory T, Iglesias-de la Cruz, M. Carmen, and Chen, Sheldon
- Published
- 2002
3. Hydrogen peroxide increases extracellular matrix mRNA through TGF-β in human mesangial cells
- Author
-
Iglesias-de la Cruz, M. Carmen, Ruiz-Torres, Piedad, Alcamí, José, Díez-Marqués, Luisa, Ortega-Velázquez, Rocío, Chen, Sheldon, Rodríguez-Puyol, Manuel, Ziyadeh, Fuad N., and Rodríguez-Puyol, Diego
- Published
- 2001
4. Effects of high glucose and TGF-β1 on the expression of collagen IV and vascular endothelial growth factor in mouse podocytes
- Author
-
Raghu Kalluri, Motohide Isono, Fuad N. Ziyadeh, Martine Kouahou, Sheldon Chen, Dong Cheol Han, Peter Mundel, and M. Carmen Iglesias-de la Cruz
- Subjects
Collagen Type IV ,Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,Proline ,Kidney Glomerulus ,Receptor, Transforming Growth Factor-beta Type I ,Gene Expression ,Dioxoles ,Endothelial Growth Factors ,Protein Serine-Threonine Kinases ,Podocyte ,Transforming Growth Factor beta1 ,chemistry.chemical_compound ,Mice ,Transforming Growth Factor beta ,Internal medicine ,medicine ,foot process ,Animals ,Diabetic Nephropathies ,Receptor ,Cells, Cultured ,Basement membrane ,Lymphokines ,biology ,Vascular Endothelial Growth Factors ,Glomerular basement membrane ,diabetic nephropathy ,epithelial cell ,Receptor, Transforming Growth Factor-beta Type II ,Cell Differentiation ,Drug Synergism ,Transforming growth factor beta ,Vascular endothelial growth factor ,Vascular endothelial growth factor A ,medicine.anatomical_structure ,Endocrinology ,Glucose ,chemistry ,glomerular basement membrane ,Nephrology ,Benzamides ,biology.protein ,Intercellular Signaling Peptides and Proteins ,proteinuria ,hypertrophy ,Activin Receptors, Type I ,Receptors, Transforming Growth Factor beta ,Transforming growth factor - Abstract
Effects of high glucose and TGF-beta1 on the expression of collagen IV and vascular endothelial growth factor in mouse podocytes.The podocyte takes center stage in the pathogenesis of glomerular basement membrane (GBM) thickening and proteinuria in diabetic glomerulopathy. In part, GBM thickening may occur when the podocyte synthesizes increased amounts of collagen IV. Proteinuria may develop if the podocyte secretes excessive amounts of vascular endothelial growth factor (VEGF), which may increase the glomerular permeability to macromolecules. The augmented production of collagen IV and VEGF may be caused by metabolic mediators of diabetes such as hyperglycemia and transforming growth factor-beta (TGF-beta).The effects of high glucose and exogenous TGF-beta1 were examined on a mouse podocyte cell line that retains its differentiated phenotype. The gene expression and protein production of certain alpha chains of collagen IV, the major isoforms of VEGF, and components of the TGF-beta system were assayed. An inhibitor of TGF-beta signaling was used to determine whether some of the high glucose effects might be mediated by the TGF-beta system.Compared with normal glucose (5.5 mmol/L), high glucose (HG, 25 mmol/L) for 14 days stimulated [3H]-proline incorporation, a measure of collagen production, by 1.8-fold, and exogenous TGF-beta1 (2 ng/mL) for 24 hours stimulated proline incorporation by 2.4-fold. Northern analysis showed that exposure to HG for 14 days increased the mRNA level of alpha1(IV) collagen by 51% and alpha5(IV) by 90%, whereas treatment with TGF-beta1 (2 ng/mL) for 24 hours decreased the mRNA level of alpha1(IV) by 36% and alpha5(IV) by 40%. Consistent with these effects on mRNA expression, Western blotting showed that HG increased alpha1(IV) protein by 44% and alpha5(IV) by 28%, while TGF-beta1 decreased alpha1(IV) protein by 29% and alpha5(IV) by 7%. In contrast to their opposing actions on alpha1 and alpha5(IV), both HG and exogenous TGF-beta1 increased alpha3(IV) collagen and VEGF, with TGF-beta1 having the greater effect. An inhibitor of the TGF-beta type I receptor (ALK5) was able to prevent the stimulation of alpha3(IV) and VEGF proteins by HG. Unlike in other renal cell types, HG did not increase TGF-beta1 mRNA or protein in the podocyte, but HG did induce the expression of the ligand-binding TGF-beta type II receptor (TbetaRII). Because HG had up-regulated TbetaRII after two weeks, the addition of physiological-dose TGF-beta1 (0.010 ng/mL) for 24 hours stimulated the production of alpha3(IV) and VEGF proteins to a greater extent in high than in normal glucose. Up-regulation of TbetaRII in the podocyte was corroborated by immunohistochemistry of the kidney cortex in the db/db mouse, a model of type 2 diabetes.High glucose and exogenous TGF-beta1 exert disparate effects on the expression of alpha1 and alpha5(IV) collagen. However, high glucose and TGF-beta1 coordinately induce the production of alpha3(IV) collagen and VEGF in the podocyte. The HG-induced increases in alpha3(IV) collagen and VEGF proteins are mediated by the TGF-beta system. By increasing the expression of TbetaRII, high glucose may augment the response of the podocyte to ambient levels of TGF-beta1.
- Full Text
- View/download PDF
5. Inhibiting albumin glycation in vivo ameliorates glomerular overexpression of TGF-β1
- Author
-
Fuad N. Ziyadeh, Soon Won Hong, Margo P. Cohen, Clyde W. Shearman, Sheldon Chen, M. Carmen Iglesias-de la Cruz, Gregory T. Lautenslager, and Elizabeth Hud
- Subjects
Glycation End Products, Advanced ,Male ,medicine.medical_specialty ,Diclofenac ,Kidney Glomerulus ,Transforming Growth Factor beta1 ,Diabetic nephropathy ,Mice ,Transforming Growth Factor beta ,Glycation ,In vivo ,Internal medicine ,Diabetes Mellitus ,medicine ,Extracellular ,Albuminuria ,Animals ,Glycated Serum Albumin ,Serum Albumin ,Protein kinase C ,transforming growth factor-β1 ,Phenylacetates ,Extracellular Matrix Proteins ,Aniline Compounds ,biology ,business.industry ,diabetic nephropathy ,Albumin ,db/db mouse ,medicine.disease ,Mice, Mutant Strains ,Fibronectin ,Db/db Mouse ,Endocrinology ,Nephrology ,biology.protein ,glycated albumin ,hyperglycemia ,business - Abstract
Inhibiting albumin glycation in vivo ameliorates glomerular overexpression of TGF-β1 . Background Glycated albumin has been causally linked to the pathobiology of diabetic renal disease through its ability to stimulate the expression of transforming growth factor-β1 (TGF-β1), activate protein kinase C (PKC) and extracellular signal-regulated kinase (ERK), and promote production of extracellular matrix proteins in cultured glomerular cells. Whether glycated albumin modulates glomerular TGF-β1 expression in vivo is not known. To address this issue, we assessed glomerular TGF-β1 expression and pathology in response to reducing the burden of glycated albumin in vivo. Methods We measured serum glycated albumin, urine protein, glomerular TGF-β1 expression and morphometry, and collagen IV and fibronectin mRNA in db/m and db/db controls and in db/db mice treated for eight weeks with a synthetic compound that inhibits the condensation of glucose with albumin. Results In situ hybridization studies showed markedly increased glomerular TGF-β1 mRNA in control db/db mice, which was significantly reduced in db/db mice treated for eight weeks with test compound. The treatment protocol, which normalized serum glycated albumin, concomitantly reduced the elevated protein excretion and the renal overexpression of mRNAs encoding fibronectin and collagen IV, and significantly decreased the mesangial matrix expansion, observed in db/db control animals. Conclusions These findings, to our knowledge, provide the first evidence that glomerular overexpression of TGF-β1 in diabetes derives at least in part from elevated glycated albumin concentrations, and can be partially suppressed by inhibiting the formation of this glycated protein. The results further suggest that glycated albumin has an important nephropathogenic role in diabetes that is operative, and can be therapeutically addressed, independent of glycemic status.
- Full Text
- View/download PDF
6. Hydrogen peroxide increases extracellular matrix mRNA through TGF-β in human mesangial cells
- Author
-
Piedad Ruiz-Torres, Sheldon Chen, Manuel Rodríguez-Puyol, Luisa Diez-Marques, Rocio Ortega-Velazquez, M. Carmen Iglesias-de la Cruz, Fuad N. Ziyadeh, José Alcamí, and Diego Rodríguez-Puyol
- Subjects
Extracellular matrix ,chemistry.chemical_compound ,Transforming Growth Factor beta ,Gene expression ,Humans ,oxidative stress ,tubulointerstitial fibrosis ,RNA, Messenger ,Northern blot ,Hydrogen peroxide ,Cells, Cultured ,chemistry.chemical_classification ,reactive oxygen species ,Extracellular Matrix Proteins ,Reactive oxygen species ,biology ,Mesangial cell ,transforming growth factor-β ,Hydrogen Peroxide ,Catalase ,Molecular biology ,renal fibrosis ,glucose oxidase ,Glomerular Mesangium ,Fibronectin ,chemistry ,Biochemistry ,Nephrology ,biology.protein ,glomerulosclerosis - Abstract
Hydrogen peroxide increases extracellular matrix mRNA through TGF-β in human mesangial cells. Background Reactive oxygen species (ROS) are excessively produced in pathologic states, including many renal diseases. Transforming growth factor-β (TGF-β) may mediate renal fibrotic injury, and ROS may act through the TGF-β pathway to exert a profibrotic effect. Methods The expression of TGF-β1 and extracellular matrix (ECM) components were assessed in cultured human mesangial cells (HMCs) incubated with glucose oxidase (GO), an enzyme that continuously generates hydrogen peroxide from glucose. A neutralizing anti–TGF-β antibody was added to test the hypothesis that hydrogen peroxide acts through activation of the TGF-β pathway to stimulate ECM expression. Results Northern blot analysis revealed significantly increased steady-state levels of TGF-β1 and ECM proteins (collagen types I, III, and IV, and fibronectin) by approximately twofold. While no significant effect on mRNA stability after treatment with GO was observed, other studies employing promoter-reporter assays, competitive-quantitative reverse transcription-polymerase chain reaction, mink lung epithelial cell proliferation assay, and TGF-β1 enzyme-linked immunosorbent assay all demonstrated significant stimulation by GO (>1.5-fold) of TGF-β1 promoter activity, mRNA level, bioactivity, and protein production, respectively. Catalase pretreatment prevented the GO-induced stimulation of TGF-β1 mRNA. When incubations were performed with a panselective neutralizing anti–TGF-β antibody, the GO-stimulated expression of ECM molecules was prevented. Conclusions GO-induced hydrogen peroxide production induces TGF-β1 synthesis and thereby increases ECM gene expression in cultured HMCs. These cellular responses may underlie the development and progression of renal diseases characterized by oxidative stress.
- Full Text
- View/download PDF
7. Inhibiting albumin glycation in vivo ameliorates glomerular overexpression of TGF-beta1.
- Author
-
Cohen, Margo P, Ziyadeh, Fuad N, Hong, Soon Won, Shearman, Clyde W, Hud, Elizabeth, Lautenslager, Gregory T, Iglesias-de la Cruz, M. Carmen, and Chen, Sheldon
- Subjects
- *
ALBUMINS , *TRANSFORMING growth factors-beta , *PROTEIN metabolism , *RESEARCH , *DICLOFENAC , *GROWTH factors , *ANIMAL experimentation , *RESEARCH methodology , *DIABETES , *MEDICAL cooperation , *EVALUATION research , *SERUM albumin , *AMINES , *COMPARATIVE studies , *CARBOCYCLIC acids , *KIDNEY glomerulus , *ALBUMINURIA , *MICE , *PHARMACODYNAMICS - Abstract
Background: Glycated albumin has been causally linked to the pathobiology of diabetic renal disease through its ability to stimulate the expression of transforming growth factor-beta1 (TGF-beta1), activate protein kinase C (PKC) and extracellular signal-regulated kinase (ERK), and promote production of extracellular matrix proteins in cultured glomerular cells. Whether glycated albumin modulates glomerular TGF-beta1 expression in vivo is not known. To address this issue, we assessed glomerular TGF-beta1 expression and pathology in response to reducing the burden of glycated albumin in vivo.Methods: We measured serum glycated albumin, urine protein, glomerular TGF-beta1 expression and morphometry, and collagen IV and fibronectin mRNA in db/m and db/db controls and in db/db mice treated for eight weeks with a synthetic compound that inhibits the condensation of glucose with albumin.Results: In situ hybridization studies showed markedly increased glomerular TGF-beta1 mRNA in control db/db mice, which was significantly reduced in db/db mice treated for eight weeks with test compound. The treatment protocol, which normalized serum glycated albumin, concomitantly reduced the elevated protein excretion and the renal overexpression of mRNAs encoding fibronectin and collagen IV, and significantly decreased the mesangial matrix expansion, observed in db/db control animals.Conclusions: These findings, to our knowledge, provide the first evidence that glomerular overexpression of TGF-beta1 in diabetes derives at least in part from elevated glycated albumin concentrations, and can be partially suppressed by inhibiting the formation of this glycated protein. The results further suggest that glycated albumin has an important nephropathogenic role in diabetes that is operative, and can be therapeutically addressed, independent of glycemic status. [ABSTRACT FROM AUTHOR]- Published
- 2002
- Full Text
- View/download PDF
8. Effects of high glucose and TGF-beta1 on the expression of collagen IV and vascular endothelial growth factor in mouse podocytes.
- Author
-
Iglesias-de la Cruz MC, Ziyadeh FN, Isono M, Kouahou M, Han DC, Kalluri R, Mundel P, and Chen S
- Subjects
- Activin Receptors, Type I analysis, Activin Receptors, Type I antagonists & inhibitors, Activin Receptors, Type I genetics, Animals, Benzamides pharmacology, Cell Differentiation, Cells, Cultured, Diabetic Nephropathies etiology, Diabetic Nephropathies physiopathology, Dioxoles pharmacology, Drug Synergism, Gene Expression drug effects, Kidney Glomerulus chemistry, Kidney Glomerulus cytology, Mice, Proline pharmacokinetics, Protein Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type I, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta analysis, Receptors, Transforming Growth Factor beta antagonists & inhibitors, Receptors, Transforming Growth Factor beta genetics, Transforming Growth Factor beta1, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors, Collagen Type IV genetics, Endothelial Growth Factors genetics, Glucose pharmacology, Intercellular Signaling Peptides and Proteins genetics, Kidney Glomerulus drug effects, Lymphokines genetics, Transforming Growth Factor beta pharmacology
- Abstract
Unlabelled: Effects of high glucose and TGF-beta1 on the expression of collagen IV and vascular endothelial growth factor in mouse podocytes., Background: The podocyte takes center stage in the pathogenesis of glomerular basement membrane (GBM) thickening and proteinuria in diabetic glomerulopathy. In part, GBM thickening may occur when the podocyte synthesizes increased amounts of collagen IV. Proteinuria may develop if the podocyte secretes excessive amounts of vascular endothelial growth factor (VEGF), which may increase the glomerular permeability to macromolecules. The augmented production of collagen IV and VEGF may be caused by metabolic mediators of diabetes such as hyperglycemia and transforming growth factor-beta (TGF-beta)., Methods: The effects of high glucose and exogenous TGF-beta1 were examined on a mouse podocyte cell line that retains its differentiated phenotype. The gene expression and protein production of certain alpha chains of collagen IV, the major isoforms of VEGF, and components of the TGF-beta system were assayed. An inhibitor of TGF-beta signaling was used to determine whether some of the high glucose effects might be mediated by the TGF-beta system., Results: Compared with normal glucose (5.5 mmol/L), high glucose (HG, 25 mmol/L) for 14 days stimulated [3H]-proline incorporation, a measure of collagen production, by 1.8-fold, and exogenous TGF-beta1 (2 ng/mL) for 24 hours stimulated proline incorporation by 2.4-fold. Northern analysis showed that exposure to HG for 14 days increased the mRNA level of alpha1(IV) collagen by 51% and alpha5(IV) by 90%, whereas treatment with TGF-beta1 (2 ng/mL) for 24 hours decreased the mRNA level of alpha1(IV) by 36% and alpha5(IV) by 40%. Consistent with these effects on mRNA expression, Western blotting showed that HG increased alpha1(IV) protein by 44% and alpha5(IV) by 28%, while TGF-beta1 decreased alpha1(IV) protein by 29% and alpha5(IV) by 7%. In contrast to their opposing actions on alpha1 and alpha5(IV), both HG and exogenous TGF-beta1 increased alpha3(IV) collagen and VEGF, with TGF-beta1 having the greater effect. An inhibitor of the TGF-beta type I receptor (ALK5) was able to prevent the stimulation of alpha3(IV) and VEGF proteins by HG. Unlike in other renal cell types, HG did not increase TGF-beta1 mRNA or protein in the podocyte, but HG did induce the expression of the ligand-binding TGF-beta type II receptor (TbetaRII). Because HG had up-regulated TbetaRII after two weeks, the addition of physiological-dose TGF-beta1 (0.010 ng/mL) for 24 hours stimulated the production of alpha3(IV) and VEGF proteins to a greater extent in high than in normal glucose. Up-regulation of TbetaRII in the podocyte was corroborated by immunohistochemistry of the kidney cortex in the db/db mouse, a model of type 2 diabetes., Conclusions: High glucose and exogenous TGF-beta1 exert disparate effects on the expression of alpha1 and alpha5(IV) collagen. However, high glucose and TGF-beta1 coordinately induce the production of alpha3(IV) collagen and VEGF in the podocyte. The HG-induced increases in alpha3(IV) collagen and VEGF proteins are mediated by the TGF-beta system. By increasing the expression of TbetaRII, high glucose may augment the response of the podocyte to ambient levels of TGF-beta1.
- Published
- 2002
- Full Text
- View/download PDF
9. Hydrogen peroxide increases extracellular matrix mRNA through TGF-beta in human mesangial cells.
- Author
-
Iglesias-De La Cruz MC, Ruiz-Torres P, Alcamí J, Díez-Marqués L, Ortega-Velázquez R, Chen S, Rodríguez-Puyol M, Ziyadeh FN, and Rodríguez-Puyol D
- Subjects
- Catalase pharmacology, Cells, Cultured, Extracellular Matrix Proteins metabolism, Glomerular Mesangium cytology, Glucose Oxidase antagonists & inhibitors, Glucose Oxidase pharmacology, Humans, Transforming Growth Factor beta genetics, Extracellular Matrix Proteins genetics, Glomerular Mesangium metabolism, Hydrogen Peroxide metabolism, RNA, Messenger metabolism, Transforming Growth Factor beta physiology
- Abstract
Background: Reactive oxygen species (ROS) are excessively produced in pathologic states, including many renal diseases. Transforming growth factor-beta (TGF-beta) may mediate renal fibrotic injury, and ROS may act through the TGF-beta pathway to exert a profibrotic effect., Methods: The expression of TGF-beta1 and extracellular matrix (ECM) components were assessed in cultured human mesangial cells (HMCs) incubated with glucose oxidase (GO), an enzyme that continuously generates hydrogen peroxide from glucose. A neutralizing anti-TGF-beta antibody was added to test the hypothesis that hydrogen peroxide acts through activation of the TGF-beta pathway to stimulate ECM expression., Results: Northern blot analysis revealed significantly increased steady-state levels of TGF-beta1 and ECM proteins (collagen types I, III, and IV, and fibronectin) by approximately twofold. While no significant effect on mRNA stability after treatment with GO was observed, other studies employing promoter-reporter assays, competitive-quantitative reverse transcription-polymerase chain reaction, mink lung epithelial cell proliferation assay, and TGF-beta1 enzyme-linked immunosorbent assay all demonstrated significant stimulation by GO (>1.5-fold) of TGF-beta1 promoter activity, mRNA level, bioactivity, and protein production, respectively. Catalase pretreatment prevented the GO-induced stimulation of TGF-beta1 mRNA. When incubations were performed with a panselective neutralizing anti-TGF-beta antibody, the GO-stimulated expression of ECM molecules was prevented., Conclusions: GO-induced hydrogen peroxide production induces TGF-beta1 synthesis and thereby increases ECM gene expression in cultured HMCs. These cellular responses may underlie the development and progression of renal diseases characterized by oxidative stress.
- Published
- 2001
- Full Text
- View/download PDF
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