Cyclosporine A sensitizes the kidney to tubulointerstitial fibrosis induced by renal warm ischemia.
BACKGROUND
Renal warm ischemic injury and immunosuppression with cyclosporin A (CsA) may contribute to chronic allograft nephropathy after cadaveric transplantation. This study establishes whether CsA can sensitize the kidney to injury and fibrosis induced by renal warm ischemia (RWI).


METHODS
The left kidney of Sprague-Dawley rats was subjected to 30 min of warm ischemia and/or intraperitoneal CsA (15 mg/kg/d) for 30 days (n=6 per group). Renal injury and fibrosis were assessed histologically together with immunohistochemistry for collagen III, transforming growth factor (TGF)-beta1, ED1 (macrophage marker), and alpha-smooth muscle actin. Renal mRNAs for collagen III, TGF-beta 1, matrix metalloproteinase (MMP)-2, and tissue inhibitor of metalloproteinase-1 together with MMP enzyme activity were also determined.


RESULTS
RWI or CsA alone produced only minor effects on renal injury and fibrosis. However, in CsA-treated rats, RWI produced a marked increase in tubulointerstitial fibrosis, as shown by the potentiation of collagen III and TGF-beta1 determined by immunochemistry and mRNA analysis. The up-regulation of tissue inhibitor of metalloproteinase-1 mRNA was associated with a decrease in MMP enzyme activity. In CsA-treated rats, RWI was also associated with an increase in inflammatory infiltrates, elevated immunostain for ED1 (indicating extensive macrophage influx), and elevated immunostain for alpha-smooth muscle actin (indicating myofibroblast activation).


CONCLUSIONS
In the rat, CsA can sensitize the kidney to fibrosis induced by renal warm ischemia. In renal transplantation, when cadaveric donor kidneys have been subjected to a period of warm ischemia, CsA may be an inappropriate choice for immunosuppressive therapy.
Ahmed
Ahmed
A
Sheffield Kidney Institute, Division of Clinical Sciences (North), University of Sheffield, Northern General Hospital, Sheffield, United Kingdom.
Huang
Linghong
L
Raftery
Andrew T
AT
Ahmed
Aimun K
AK
Fahmy
Hossam
H
El Nahas
A Meguid
AM
Haylor
John L
JL
D000818:Animals; D024061:Collagen Type III / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D005355:Fibrosis; D006358:Hot Temperature; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007511:Ischemia / Q000473:pathology* / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D016030:Kidney Transplantation; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D009395:Nephritis, Interstitial / Q000473:pathology* / Q000503:physiopathology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D024061:Collagen Type III; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016572:Cyclosporine; D020778:Matrix Metalloproteinase 2