NDT Advance Access originally published online on August 2, 2005
Nephrology Dialysis Transplantation 2005 20(11):2321-2332; doi:10.1093/ndt/gfi042
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Early proximal tubule injury in experimental aristolochic acid nephropathy: functional and histological studies
1 Laboratory for Research on Peptide Metabolism, Faculty of Medicine, 2 Department of Nephrology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium and 3 Section of Molecular Carcinogenesis, Institute of Cancer Research, Sutton, Surrey, UK
Correspondence and offprint requests to: Catherine Lebeau, Laboratory for Research on Peptide Metabolism, Université Libre de Bruxelles, Campus Erasme CP 603, Route de Lennik 808, B-1070 Brussels, Belgium. Email: clebeau{at}ulb.ac.be
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-ß-D-glucosaminidase, 
-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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