Expression of TGF-beta and fibrogenic genes in transplant recipients with tacrolimus and cyclosporine nephrotoxicity.
BACKGROUND
Long-term treatment with cyclosporine (CsA) or tacrolimus (Tac) results in chronic nephrotoxicity. Transforming growth factor-beta (TGF-beta) and other pro-fibrogenic molecules have been known to contribute to this side effect. A comparison of intrarenal expression of TGF-beta and other fibrogenic genes in biopsies from patients with either CsA or Tac nephrotoxicity have not been documented. This study compared the expression of TGF-beta, collagen, fibronectin, metalloproteinases (MMP-2, -9), tissue inhibitors of metalloproteinases (TIMP-2) and osteopontin in renal biopsies obtained from renal transplant recipients treated with either CsA or Tac as primary immunosuppressive agents.


METHODS
Using RT-PCR, intrarenal expression of TGF-beta, collagen, fibronectin, MMP-2, MMP-9 and TIMP-2 were studied in renal biopsies from patients with histological diagnosis of CsA or Tac nephrotoxicity and acute rejection. TGF-beta protein expression was studied by staining section of biopsies with anti-TGF-beta antibody.


RESULTS
Intrarenal expression of TGF-beta, collagen, fibronectin, MMP-2, TIMP-2, and osteopontin were significantly increased in patients treated with Tac nephrotoxicity compared with CsA nephrotoxicity. The intrarenal mRNA expression of these genes was higher in patients diagnosed with Tac/CsA nephrotoxicity compared to acute rejection.


CONCLUSIONS
This study compares the intrarenal expression of TGF-beta and profibrogenic genes in renal transplant recipients treated with Tac and CsA. The results show that patients diagnosed with Tac nephrotoxicity exhibit increased expression of profibrogenic genes compared to CsA nephrotoxicity.
Khanna
Ashwani
A
Department of Medicine, Division of Nephrology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. akkhanna@mcw.edu
Plummer
Matthew
M
Bromberek
Cathy
C
Bresnahan
Barbara
B
Hariharan
Sundaram
S
D001706:Biopsy; D003094:Collagen / Q000235:genetics; D016572:Cyclosporine / Q000009:adverse effects*; D005353:Fibronectins / Q000235:genetics; D015870:Gene Expression; D006084:Graft Rejection / Q000188:drug therapy; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007668:Kidney / Q000502:physiology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000601:surgery; D016030:Kidney Transplantation; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D053495:Osteopontin; D012333:RNA, Messenger / Q000032:analysis; D012795:Sialoglycoproteins / Q000235:genetics; D016559:Tacrolimus / Q000009:adverse effects*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics*
D005353:Fibronectins; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; D016212:Transforming Growth Factor beta; D053495:Osteopontin; D019716:Tissue Inhibitor of Metalloproteinase-2; D016572:Cyclosporine; D003094:Collagen; D020780:Matrix Metalloproteinase 9; D016559:Tacrolimus