RESUMO
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-beta (TGF-beta) 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-beta in part mediates both the immunosuppressive and nephrotoxic effects of cyclosporine, recipients were treated with cyclosporine with and without anti-TGF-beta antibody to determine whether anti-TGF-beta antibody could reduce the nephrotoxic effects of cyclosporine. Intrarenal expression of TGF-beta, 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-beta protein was studied by immunohistochemistry and with the use of ELISA to quantify circulating levels of TGF-beta protein in plasma. Cyclosporine-induced graft survival (immunosuppressive effect) was abrogated with a higher concentration (2.5 mg/kg) of anti-TGF-beta 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-beta 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-beta antibody to ameliorate cyclosporine-associated nephrotoxicity in cardiac transplant recipients.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Ciclosporina/toxicidade , Transplante de Coração/efeitos adversos , Imunossupressores/toxicidade , Nefropatias/prevenção & controle , Fator de Crescimento Transformador beta/antagonistas & inibidores , Transplante Homólogo/efeitos adversos , Animais , Anticorpos Monoclonais/farmacologia , Colágeno/biossíntese , Colágeno/genética , Ciclosporina/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Fibronectinas/biossíntese , Fibronectinas/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Transplante de Coração/imunologia , Imunossupressores/uso terapêutico , Imunoterapia , Rim/efeitos dos fármacos , Rim/metabolismo , Nefropatias/induzido quimicamente , Nefropatias/genética , Nefropatias/metabolismo , Testes de Função Renal , Metaloproteinase 1 da Matriz/biossíntese , Metaloproteinase 1 da Matriz/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Endogâmicos Lew , Ratos Endogâmicos WF , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Inibidor Tecidual de Metaloproteinase-2/biossíntese , Inibidor Tecidual de Metaloproteinase-2/genética , Fator de Crescimento Transformador beta/biossíntese , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologia , Transplante Heterotópico , Transplante Homólogo/imunologiaRESUMO
BACKGROUND: Long-term treatment of heart transplantation recipients with cyclosporine (CsA) results in chronic nephrotoxic effects, which frequently lead to progressive renal failure. Transforming growth factor (TGF)-beta and other fibrogenic molecules are leading candidates for these effects, because CsA is known to induce TGF-beta. In this study we compared the expression of TGF-beta, collagen, fibronectin, metalloproteinases, and tissue inhibitors of metalloproteinases in kidneys from recipients of heterotopic heart transplants treated with CsA for 30 and 180 days. METHODS: Using a clinically relevant experimental rodent model (strain combination Wistar Furth [RT1u] into Lewis [RT1l]), heterotopic heart transplantation was performed, creating disparate cardiac allografts. The transplant study population was divided into three groups: controls and those receiving CsA immunosuppression therapy to maintain graft survival for 30-day and 180-day periods. Comparisons were made of intrarenal expression of TGF-beta, collagen, fibronectin, metalloproteinase-2 (MMP-2), MMP-9, and tissue inhibitor of MMP-2, using reverse transcriptase-polymerase chain reaction. Intrarenal expression of TGF-beta protein was also compared using immunochemical staining technique, and circulating levels of TGF-beta protein were quantified by ELISA. RESULTS: Intrarenal expression of TGF-beta, collagen, fibronectin, MMP-2, MMP-9, and tissue inhibitor of MMP-2 was significantly increased in rats treated with CsA for 180 days compared with untreated rats and those treated for 30 days. Circulating levels and intrarenal expression of TGF-beta were also significantly increased in rats treated for 180 days. CONCLUSION: Posttransplantation nephrotoxicity in cardiac transplant recipients treated with CsA for a long term is related to increased expression of TGF-beta and other fibrogenic genes. Therapies designed to inhibit expression of TGF-beta could ameliorate CsA-associated nephrotoxicity in cardiac transplant recipients.