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

Abstract

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.

Prophylactic role of curcumin against cyclosporine-induced nephrotoxicity: Histological and immunohistological study

“…These observations were in agreement with Kang et al (2001). Li et al (2003) and Khanna et al (2004) detected tubular and vascular changes, including thickening of basement membranes and increased PAS staining of vascular structures in cyclosporine-treated animals. They added that afferent arteriolopathy was manifested by replacement of smooth muscle cells of afferent glomerular arteriole by a PAS-positive material.…”

“…The renal damage induced by CsA is time and dose dependant (Khanna et al 2004). Curcumin was reported to be a regulator of the expression of inflammatory enzymes, cytokines, adhesion molecules, and cell survival proteins by modulating the activation of various transcription factors (Goel et al 2008).…”

Reactive Oxygen and Reactive Nitrogen as Signaling Molecules for Caspase 3 Activation in Acute Cardiac Transplant Rejection

“…In the first series, allograft recipients were treated with CsA to show that caspase 3 activation was due to alloimmune activation. We previously showed that cardiac allografts survived to at least 117 days when given continuously at this dose (10) and that the increase in IFN-␥ and CD3 mRNA in a mixed splenocyte culture was prevented in cells taken from CsA-treated rats at posttransplant day 6 and stimulated ex vivo without added CsA (24). The latter indicates that the dose used effectively blocks both cytokine gene expression and lymphocyte activation.…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…To further complicate matters, other data suggest that outcomes may depend on the degree of TGFantagonism. Thus, cyclosporine-induced heterotopic heart transplantation survival was reduced by higher doses of TGF-antibody, whereas a lower antibody concentration inhibited both cyclosporine-induced expression of fibrogenic molecules and renal toxicity (280).…”