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NDT Advance Access published online on August 2, 2005
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfi042
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received April 6, 2005
Accepted July 5, 2005

Original Articles

Early proximal tubule injury in experimental aristolochic acid nephropathy: functional and histological studies

Catherine Lebeau 1*, Frédéric D. Debelle 2, Volker M. Arlt 3, Agnieszka Pozdzik 1, Eric G. De Prez 1, David H. Phillips 3, Monique M. Deschodt-Lanckman 1, Jean-Louis Vanherweghem 4, and Joëlle L. Nortier 2

1 Laboratory for Research on Peptide Metabolism, Faculty of Medicine, Brussels, Belgium
2 Laboratory for Research on Peptide Metabolism, Faculty of Medicine, Brussels, Belgium; Department of Nephrology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
3 Section of Molecular Carcinogenesis, Institute of Cancer Research, Sutton, Surrey, UK
4 Department of Nephrology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium

* To whom correspondence should be addressed.
Catherine Lebeau, E-mail: clebeau{at}ulb.ac.be



  Abstract

Background. Aristolochic acid (AA), the plant extract of Aristolochia species, is involved in the onset of progressive tubulointerstitial renal fibrosis in humans. Clinical and in vitro findings have previously suggested that the proximal tubule was the target of AA.

Methods. Using a rat model of AA nephropathy, the proximal tubular lesions induced by daily subcutaneous injections of AA for 35 or 5 days were characterized biochemically and histologically. Urinary excretion of proteins, albumin, low molecular weight proteins, N-acetyl-{beta}-d-glucosaminidase, {alpha}-glutathione S-transferase, leucine aminopeptidase and neutral endopeptidase (NEP) was determined and related to histological conventional findings and immunostainings of NEP and megalin.

Results. In both protocols, an acute phase of release of urinary markers was observed within the first 3 days of AA treatment in parallel with a significant increase of specific AA-related DNA adducts reflecting early tubular intoxication. A dramatic loss of the proximal tubule brush border was histologically confirmed, while the expression of megalin decreased at the damaged apical epithelium (mainly of the S3 segment).

Conclusion. Proximal tubule injury occurs early after AA intoxication in rats, with a link between specific AA-DNA adduct formation, decreased megalin expression and inhibition of receptor-mediated endocytosis of low molecular weight proteins, bringing in vivo confirmation of previous in vitro studies.

Keywords: aristolochic acid nephropathy; low molecular weight proteins; megalin; neutral endopeptidase; proximal tubule injury; tubular proteinuria.
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