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


CONCLUSIONS
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.
Lebeau
Catherine
C
Laboratory for Research on Peptide Metabolism, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium. clebeau@ulb.ac.be
Debelle
Frédéric D
FD
Arlt
Volker M
VM
Pozdzik
Agnieszka
A
De Prez
Eric G
EG
Phillips
David H
DH
Deschodt-Lanckman
Monique M
MM
Vanherweghem
Jean-Louis
JL
Nortier
Joëlle L
JL
D000118:Acetylglucosaminidase / Q000652:urine; D000418:Albumins / Q000378:metabolism; D000818:Animals; D034341:Aristolochic Acids / Q000633:toxicity*; D015415:Biomarkers / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000235:genetics; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005982:Glutathione Transferase / Q000652:urine; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000652:urine; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007931:Leucyl Aminopeptidase / Q000652:urine; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism; D008297:Male; D015260:Neprilysin / Q000652:urine; D051381:Rats; D017208:Rats, Wistar
D000418:Albumins; D034341:Aristolochic Acids; D015415:Biomarkers; D002273:Carcinogens; D018736:DNA Adducts; D026561:Low Density Lipoprotein Receptor-Related Protein-2; C000228:aristolochic acid I; D005982:Glutathione Transferase; D000118:Acetylglucosaminidase; D007931:Leucyl Aminopeptidase; D015260:Neprilysin