RESUMEN
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.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Ciclosporina/toxicidad , Trasplante de Corazón/efectos adversos , Inmunosupresores/toxicidad , Enfermedades Renales/prevención & control , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Trasplante Homólogo/efectos adversos , Animales , Anticuerpos Monoclonales/farmacología , Colágeno/biosíntesis , Colágeno/genética , Ciclosporina/uso terapéutico , Evaluación Preclínica de Medicamentos , Fibronectinas/biosíntesis , Fibronectinas/genética , Regulación de la Expresión Génica/efectos de los fármacos , Trasplante de Corazón/inmunología , Inmunosupresores/uso terapéutico , Inmunoterapia , Riñón/efectos de los fármacos , Riñón/metabolismo , Enfermedades Renales/inducido químicamente , Enfermedades Renales/genética , Enfermedades Renales/metabolismo , Pruebas de Función Renal , Metaloproteinasa 1 de la Matriz/biosíntesis , Metaloproteinasa 1 de la Matriz/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Ratas Endogámicas Lew , Ratas Endogámicas WF , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Inhibidor Tisular de Metaloproteinasa-2/biosíntesis , Inhibidor Tisular de Metaloproteinasa-2/genética , Factor de Crecimiento Transformador beta/biosíntesis , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/inmunología , Trasplante Heterotópico , Trasplante Homólogo/inmunologíaRESUMEN
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.