Effect of anti-transforming growth factor-βbgr; antibodies in cyclosporine-induced renal dysfunction

Islam, Muhammad; Burke, James F.; McGowan, Tracy; Zhu, Yanqing; Dunn, Stephen; McCue, Peter A.; Kanalas, John J.; Sharma, Kumar

doi:10.1046/j.1523-1755.2001.059002498.x

Cited by 114 publications

(86 citation statements)

References 24 publications

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“…35 A number of studies have implicated TGF-␤ as a key mediator of cyclosporine-induced nephrotoxicity, but definitive evidence has only recently been reported. Our laboratory 15 and those of others 36,37 have examined the effects of administering TGF-␤-neutralizing antibodies to nontransplantation models of cyclosporine nephrotoxicity. These studies have shown that blocking TGF-␤ can normalize the expression of collagen types III and I and substantially reduce overall tissue fibrosis when examined histologically.…”

Section: Discussionmentioning

confidence: 99%

Anti–Transforming Growth Factor Antibody at Low but Not High Doses Limits Cyclosporine-Mediated Nephrotoxicity Without Altering Rat Cardiac Allograft Survival

et al. 2004

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Background-Long-term treatment of cardiac transplant recipients with cyclosporine results in a progressive decline in kidney function in a large number of patients. This complication is one of the most important prognostic parameters that determine the outcome of cardiac transplantation. Transforming growth factor-␤ (TGF-␤) is one of the most potent mediators of the fibrogenic effects of cyclosporine. Methods and Results-With the use of an experimental rodent model, heterotopic heart transplantation was performed, creating histocompatibility-disparate allografts. Because TGF-␤ in part mediates both the immunosuppressive and nephrotoxic effects of cyclosporine, recipients were treated with cyclosporine with and without anti-TGF-␤ antibody to determine whether anti-TGF-␤ antibody could reduce the nephrotoxic effects of cyclosporine. Intrarenal expression of TGF-␤, collagen, fibronectin, matrix metalloproteinase-2, and tissue inhibitor of metalloproteinase-2 was studied with the use of reverse transcription-polymerase chain reaction. Intrarenal expression of TGF-␤ protein was studied by immunohistochemistry and with the use of ELISA to quantify circulating levels of TGF-␤ protein in plasma. Cyclosporine-induced graft survival (immunosuppressive effect) was abrogated with a higher concentration (2.5 mg/kg) of anti-TGF-␤ antibody, whereas a lower concentration (1 mg/kg) inhibited both cyclosporine-induced expression of fibrogenic molecules and renal toxicity. Conclusions-These results provide credence to the pivotal role of TGF-␤ in immunosuppression-associated renal toxicity in recipients of cardiac transplantation. Furthermore, these findings support a potentially significant therapeutic use of optimal concentration of anti-TGF-␤ antibody to ameliorate cyclosporine-associated nephrotoxicity in cardiac transplant recipients.

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Section: Discussionmentioning

confidence: 99%

Anti–Transforming Growth Factor Antibody at Low but Not High Doses Limits Cyclosporine-Mediated Nephrotoxicity Without Altering Rat Cardiac Allograft Survival

et al. 2004

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“…Cyclosporin A stimulates levels of circulating TGF-␤ in vivo (Khanna et al, 1997), and enhances TGF-␤ production by renal cells and lymphocytes (Ahuja et al, 1995;Prashar et al, 1995;Young et al, 1995;Wolf et al, 1996). This results in increased collagenous extracellular matrix synthesis and deposition in the glomeruli of the kidney, as demonstrated by studies with anti-TGF-␤1 antibodies that block renal fibrosis and renal dysfunction (Shihab et al, 1996;Islam et al, 2001). Taken together, these studies suggest that cyclosporin A stimulates TGF-␤ production that, in turn, leads to kidney fibrosis and nephropathy.…”

Section: Unique Aspects Of Gingival Fibroblast Metabolismmentioning

confidence: 91%

Connective Tissue Metabolism and Gingival Overgrowth

Trackman

Kantarcı

2004

Critical Reviews in Oral Biology & Medicine

136

152

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Gingival overgrowth occurs mainly as a result of certain anti-seizure, immunosuppressive, or antihypertensive drug therapies. Excess gingival tissues impede oral function and are disfiguring. Effective oral hygiene is compromised in the presence of gingival overgrowth, and it is now recognized that this may have negative implications for the systemic health of affected patients. Recent studies indicate that cytokine balances are abnormal in drug-induced forms of gingival overgrowth. Data supporting molecular and cellular characteristics that distinguish different forms of gingival overgrowth are summarized, and aspects of gingival fibroblast extracellular matrix metabolism that are unique to gingival tissues and cells are reviewed. Abnormal cytokine balances derived principally from lymphocytes and macrophages, and unique aspects of gingival extracellular matrix metabolism, are elements of a working model presented to facilitate our gaining a better understanding of mechanisms and of the tissue specificity of gingival overgrowth.

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“…One potential mechanism for upregulation of matrix appears to be via the pleotropic cytokine TGFβ. Not only is TGFβ production increased along with matrix proteins in cultured cells after calcineurin inhibition [4], but CsA-mediated fibrosis can be reduced by neutralizing TGFβ antibody in vivo [5,6]. From these experiments, it is reasonable to conclude that calcineurin activity negatively regulates TGFβ and, consequently, extracellular matrix.…”

Section: Introductionmentioning

confidence: 90%

NFATc is required for TGFβ-mediated transcriptional regulation of fibronectin

Cobbs

Gooch

2007

Biochemical and Biophysical Research Communications

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Calcineurin is an important regulator of extracellular matrix (ECM) accumulation in the kidney but functions in a cell-specific manner. Previously, we identified a novel role for calcineurin in mesangial cells where calcineurin activity is required for TGFβ-mediated induction of fibronectin expression. In this study we examined the role of the calcineurin substrate NFATc in transcriptional regulation of fibronectin. First, inhibition of calcineurin blocks TGFβ induction of the fibronectin promoter. Moreover, expression of constitutively active calcineurin in mesangial cells is sufficient to increase fibronectin transcription. Next, inhibition of the calcineurin substrate NFATc1 blocked TGFβ-mediated activation of the fibronectin promoter. Finally, stable expression of a dominant negative NFATc protein reduced transcriptional activation of the promoter and inhibited TGFβ-mediated fibronectin expression. In conclusion, TGFß activation of calcineurin in mesangial cells results in regulation of ECM accumulation at least in part by direct transcriptional activity of NFATc on the fibronectin promoter.

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Effect of anti-transforming growth factor-βbgr; antibodies in cyclosporine-induced renal dysfunction

Cited by 114 publications

References 24 publications

Anti–Transforming Growth Factor Antibody at Low but Not High Doses Limits Cyclosporine-Mediated Nephrotoxicity Without Altering Rat Cardiac Allograft Survival

Anti–Transforming Growth Factor Antibody at Low but Not High Doses Limits Cyclosporine-Mediated Nephrotoxicity Without Altering Rat Cardiac Allograft Survival

Connective Tissue Metabolism and Gingival Overgrowth

NFATc is required for TGFβ-mediated transcriptional regulation of fibronectin

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