Analysis of transforming growth factor-beta and profibrogenic molecules in a rat cardiac allograft model treated with cyclosporine.
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.


CONCLUSIONS
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.
Khanna
Ashwani K
AK
Department of Medicine (Nephrology), Medical College of Wisconsin, Milwaukee, Wisconsin 53215, USA.
Hosenpud
Jessica S
JS
Plummer
Matthew S
MS
Hosenpud
Jeffrey D
JD
D000818:Animals; D016572:Cyclosporine / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007668:Kidney / Q000201:enzymology / Q000276:immunology / Q000502:physiology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D023421:Models, Animal; D051381:Rats; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000032:analysis* / Q000097:blood / Q000235:genetics; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous / Q000276:immunology / Q000502:physiology
D007166:Immunosuppressive Agents; D016212:Transforming Growth Factor beta; D019716:Tissue Inhibitor of Metalloproteinase-2; D016572:Cyclosporine; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9