Papel do macrófago na nefrotoxicidade crônica induzida pela ciclosporina A.

AUTOR(ES)

Carla Patricia Carlos

DATA DE PUBLICAÇÃO

2009

RESUMO

The aim of this study was to investigate the role of macrophage, nitric oxide pathway and oxidative stress on chronic cyclosporin (CsA) nephrotoxicity. Methods: Macrophages were depleted by clodronate liposomes (CL). Male rats on a low salt diet, were distributed in 3 groups: vehicle (VH, olive oil), CsA 7.5 mg/Kg/day (CsA, 21 days), or CsA plus CL (CsA-CL, 1 ml intraperitoneal, 5mg/ml) given on d -4, 1, 4, 11 and 18 of CsA treatment). On day 22 were evaluated glomerular filtration rate, renal blood, renal tubulointerstitial fibrosis, CsA blood level and malondialdehyde. Renal tissue immunohistochemistry for macrophage (ED-1), inducible NO synthase (iNOS), TGF-β, NF-kβ, -SMA, vimentin and nitrotyrosine was assessed. Results: Macrophage depletion attenuated CsA-induced reductions in glomerular filtration rate (0.250.09 CsA vs 1.100.18 VH vs 0.440.04 CsA-CL, p<0.001) and in renal blood flow (1.60.72 CsA vs 3.20.75 VH vs 2.910.53 CsA-CL, p<0.001), tubulointerstitial fibrosis development (121.9 CsA vs 5.61.7 VH vs 7.80.4 CsA-CL, p<0.001) and malondialdehyde increase (2,436992 CsA vs 53881 VH vs 1,456743 CsA-CL, p<0.001), increases in NF-kβ (2.60.3 CsA vs 1.10.1 VH vs 1.40.5 CsA-CL, p<0.001), TGF-β (2.40.3 CsA vs 0.20.4 VH vs 1.10.2 CsA-CL, p<0.01), vimentin (1.80.6 CsA vs 0.10.1 VH vs 0.40.3 CsA-CL, p<0.001), iNOS (4417 CsA vs 72 VH vs 114 CsA-CL, p<0.001) and nitrotyrosine (1.90.4 CsA vs 0.20.1 VH vs 0.20.1 CsA-CL, p<0.01). CL did not affect increases in glomerular and tubulointerstitial -SMA. ED-1 increase was prevented by CL (246 CsA vs 21 VH vs 41 CsA-CL, p<0.001). CsA blood level was not affected by CL. Conclusion: The influx of macrophages to renal tissue on the cyclosporin exposure contributes to nephrotoxicity. This effect was likely due to nitric oxide pathway and oxidative stress modulation.

ASSUNTO(S)

nephrotoxicity oxidative stress ratas nitric oxide estresse oxidativo rat rats macrophage macrophages Óxido nítrico cyclosporine ciclosporina rato nefrologia cyclosporin nefrotoxicidade ratos macrófago macrófagos

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