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- Title
Aristolochic acid impedes endocytosis and induces DNA adducts in proximal tubule cells.
- Authors
Lebeau, Catherine; Arlt, Volker M.; Schmeiser, Heinz H.; Boom, Alain; Verroust, Pierre J.; Devuyst, Olivier; Beauwens, Renaud; Lebeau, C; Arlt, V M; Schmeiser, H H; Boom, A; Verroust, P J; Devuyst, O; Beauwens, R
- Abstract
<bold>Background: </bold>Aristolochic acid (AA), present in Aristolochia plants, appears to be the toxin responsible for Chinese herbs nephropathy (CHN), a rapidly progressive tubulointerstitial nephritis. One of the earliest sign of CHN is the urinary excretion of low-molecular-weight proteins (LMWP), suggesting that AA is toxic to proximal tubules (PT).<bold>Methods: </bold>The effects of AA on PT functions including reabsorption of LMWP were investigated on the well-established opossum kidney (OK) cell line, a model for PT, and compared with those of the classical PT toxin cadmium chloride (CdCl2).<bold>Results: </bold>OK cell monolayers internalized albumin and beta2-microglobulin by receptor-mediated endocytosis, both proteins apparently competing for the same receptor, a complex of megalin and cubulin. The process was significantly impaired by 24-hour preincubation with AA (10 or 20 micromol/L) or CdCl2 (15 micromol/L). Furthermore, 24-hour exposure to AA followed by its removal during one to six days led to a persistent inhibition of the uptake of albumin, in contrast to the substantial recovery observed after CdCl2 removal. Neither AA nor CdCl2 affected cell viability, Na+-glucose cotransport or total rate of protein synthesis. AA significantly decreased megalin expression and formed specific DNA adducts in OK cells, similar to those found in kidneys from CHN patients.<bold>Conclusions: </bold>The present data support the involvement of AA in the early PT dysfunction found in CHN; furthermore, they suggest a causal relationship between DNA adduct formation, decreased megalin expression, and inhibition of receptor-mediated endocytosis of LMWP.
- Subjects
NEPHROTOXICOLOGY; PHYSIOLOGICAL effects of cadmium; KIDNEY tubules
- Publication
Kidney International, 2001, Vol 60, Issue 4, p1332
- ISSN
0085-2538
- Publication type
journal article
- DOI
10.1046/j.1523-1755.2001.00938.x