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 admi nistration has to be combined with a low salt diet, which causes hemodynami c changes and RAS up-regulation. Materials and 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 treate d 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) a nd collagen III expression, and on TGF-beta-(1), collagen III and IV deposi tion. Sacrifices were performed after 2, 4, 8 and 12 weeks (wks) and kidney s were harvested for immunohistological studies and RT/PCR analysis. Result s: 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 exte nsion at the 4th week to medullary rays and to cortex interstitium, The dep osition paralleled the renal collagen III mRNA up-regulation: it was signif icantly higher in group 1 than in group 2 (p < 0.009 at 2nd wk: P < 0.016 a t 4th wk), Collagen IV deposition did not differ between groups at any poin t. Conclusions: Our results suggest that chronic CsA administration can ind uce. in normal fed rats, the process of interstitial fibrogenesis through T GF-beta non-related mechanisms.