1. ¹Experimental Nephrology Unit, Faculty of Medicine, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium
2. ²Department of Pathology, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium
3. ³Department of Nephrology, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium
4. ⁴Laboratory of Toxicology, Institute of Pharmacy, Université Libre de Bruxelles (ULB), Brussels, Belgium
5. ⁵Menselijke Anatomie, Vrije Universiteit Brussel, Brussels, Belgium
6. ⁶Department of Nephrology, Vrije Universiteit Brussel, Brussels, Belgium

Correspondence: JL Nortier, Department of Nephrology, Erasme Hospital, Université Libre de Bruxelles (ULB), Route de Lennik 808, B-1070 Brussels, Belgium. E-mail: jnortier@ulb.ac.be

Received 23 January 2007; Revised 24 August 2007; Accepted 8 October 2007; Published online 19 December 2007.

Abstract

Aristolochic acid contamination in herbal remedies leads to interstitial fibrosis, tubular atrophy, and renal failure in humans. To study the cellular mechanisms contributing to the pathophysiology of this renal disease, we studied Wistar rats treated with aristolochic acid and measured tubular and interstitial cell proliferation, epithelial/mesenchymal cell marker expression, tubular membrane integrity, myofibroblast accumulation, oxidative stress, mitochondrial damage, tubular apoptosis, and fibrosis. Oxidative stress, a loss of cadherin concomitant with vimentin expression, basement membrane denudation with active caspase-3 expression, and mitochondrial injury within tubular cells were evident within 5 days of administration of the toxin. During the chronic phase, interstitial mesenchymal cells accumulated in areas of collagen deposits. Impaired regeneration and apoptosis of proximal tubular cells resulted in tubule atrophy with a near absence of dedifferentiated cell transmembrane migration. We suggest that resident fibroblast activation plays a critical role in the process of renal fibrosis during aristolochic acid toxicity.