Macrophage Depletion Attenuates Chronic Cyclosporine A Nephrotoxicity

Autor(es)

Carlos, Carla P. ^[1] ; Mendes, Gloria E. F. ^[1] ; Miquelin, Andre R. ^[1] ; Luz, Marcus A. M. ^[1] ; da Silva, Cleonice G. A. ^[2] ; van Rooijen, Nico ^[3] ; Coimbra, Terezila M. ^[2] ; Burdmann, Emmanuel A. ^[1]

Afiliação do(s) autor(es)

^[1] Sao Jose Rio Preto Med Sch, Div Nephrol, Sao Jose Do Rio Preto, SP - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Physiol, BR-14049 Ribeirao Preto - Brazil

^[3] Vrije Univ Amsterdam, Dept Mol Cell Biol, Fac Med, Amsterdam - Netherlands

• Tipo de documento: Artigo Científico
• Fonte: TRANSPLANTATION; v. 89, n. 11, p. 1362-1370, JUN 15 2010.
• Citações Web of Science: 17

Resumo

Background. Cyclosporine A (CsA)-induced chronic nephrotoxicity is characterized by renal dysfunction and interstitial fibrosis. Early and progressive renal macrophage influx, correlating with latter interstitial fibrotic areas, has been associated with CsA treatment. This study investigated the role of macrophages, the nitric oxide (NO) pathway, and the oxidative stress on chronic CsA nephrotoxicity. Methods. The macrophages were depleted by clodronate liposomes. Animals were distributed into four groups: vehicle (olive oil for 21 days), CsA 7.5 mg/kg per day (21 days), CsA plus clodronate (5 mg/mL intraperitoneally on days -4, 1, 4, 11, and 18 of CsA treatment), or vehicle plus clodronate. On day 22, glomerular filtration rate, renal blood flow, renal tubulointerstitial fibrosis, CsA blood levels, serum malondialdehyde and renal tissue immunohistochemistry for macrophages, inducible NO synthase, transforming growth factor-beta, nuclear factor-k beta, alpha-smooth muscle actin, vimentin, and nitrotyrosine were assessed. Results. CsA-induced increase in the macrophage was prevented by clodronate. Macrophage depletion attenuated the reductions in the glomerular filtration rate and renal blood flow, the development of tubulointerstitial fibrosis, malondialdehyde increase and increases in nuclear factor-k beta, transforming growth factor-beta, vimentin, inducible NO synthase, and nitrotyrosine expression provoked by CsA. Clodronate did not affect alpha-smooth muscle actin expression and CsA blood levels. Conclusions. Renal macrophage influx plays an important role in CsA-induced chronic nephrotoxicity. The NO pathway and oxidative stress are likely mechanisms involved in the genesis of this form of renal injury. (AU)

• Processo FAPESP: 05/02513-9 - Papel do macrofago na nefrotoxicidade cronica induzida pela ciclosporina a.
• Beneficiário: André Rodrigo Miquelin
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 05/00867-8 - Papel do macrofago na nefrotoxicidade cronica induzida pela ciclosporina a.
• Beneficiário: Carla Patrícia Carlos
• Modalidade de apoio: Bolsas no Brasil - Doutorado