Direct effect of chronic cyclosporine treatment on collagen III mRNA expression and deposition in rat kidneys.
BACKGROUND
It is hypothesized that in acute and chronic CsA nephrotoxicity, in vivo models CsA side-effects are mediated by Renin-Angiotensin II (RAS)-TGF-beta-1 pathway. However, to induce chronic nephrotoxicity, CsA administration has to be combined with a low salt diet, which causes hemodynamic changes and RAS up-regulation.


METHODS
In order to define any direct correlation between CsA and nephrotoxicity, we studied in normal sodium fed rats, the chronic effects of CsA administration (group-1 treated with 12.5 mg/Kg/day of CsA subcutaneously; group 2 received daily placebo; group 3 interrupted CsA injection after 60 days), on renal TGF-beta-1 and collagen III expression, and on TGF-beta-1, collagen III and IV deposition. Sacrifices were performed after 2, 4, 8 and 12 weeks (wks) and kidneys were harvested for immunohistological studies and RT/PCR analysis.


RESULTS
No difference of TGF-beta-1 expression and deposition was found among groups. Starting from the 2nd week of treatment, an increased collagen III deposition was evident in vessels and in outer medulla with subsequent extension at the 4th week to medullary rays and to cortex interstitium. The deposition paralleled the renal collagen III mRNA up-regulation: it was significantly higher in group 1 than in group 2 (p < 0.009 at 2nd wk; p < 0.016 at 4th wk). Collagen IV deposition did not differ between groups at any point.


CONCLUSIONS
Our results suggest that chronic CsA administration can induce, in normal fed rats, the process of interstitial fibrogenesis through TGF-beta non-related mechanisms.
Ceol
M
M
Dipartimento di Scienze Mediche e Chirurgiche, Università di Padova, Italy.
Anglani
F
F
Vianello
D
D
Murer
L
L
Del Prete
D
D
Forino
M
M
Favaro
S
S
Gambaro
G
G
D'Angelo
A
A
D000818:Animals; D003094:Collagen / Q000235:genetics*; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000378:metabolism
D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D016572:Cyclosporine; D003094:Collagen