Journal Article

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

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

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 20, issue 11, pages 2321-2332
Published in print November 2005 | ISSN: 0931-0509
Published online August 2005 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfi042
Early proximal tubule injury in experimental aristolochic acid nephropathy: functional and histological studies

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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-β-d-glucosaminidase, α-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

Journal Article.  5143 words.  Illustrated.

Subjects: Nephrology

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