Macrophage depletion attenuates chronic cyclosporine A nephrotoxicity.

Abstract:

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-kbeta, 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-kbeta, 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.

journal_name

Transplantation

journal_title

Transplantation

authors

Carlos CP,Mendes GE,Miquelin AR,Luz MA,da Silva CG,van Rooijen N,Coimbra TM,Burdmann EA

doi

10.1097/tp.0b013e3181da0587

subject

Has Abstract

pub_date

2010-06-15 00:00:00

pages

1362-70

issue

11

eissn

0041-1337

issn

1534-6080

journal_volume

89

pub_type

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