Aristolochic acid induces proximal tubule apoptosis and epithelial to mesenchymal transformation.
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.
Pozdzik
A A
AA
Experimental Nephrology Unit, Faculty of Medicine, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium.
Salmon
I J
IJ
Debelle
F D
FD
Decaestecker
C
C
Van den Branden
C
C
Verbeelen
D
D
Deschodt-Lanckman
M M
MM
Vanherweghem
J-L
JL
Nortier
J L
JL
D000818:Animals; D017209:Apoptosis; D034341:Aristolochic Acids / Q000633:toxicity*; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000652:urine; D003094:Collagen / Q000032:analysis / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D000070819:Discoidin Domain Receptor 1; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D005355:Fibrosis; D019394:Ki-67 Antigen / Q000032:analysis; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008648:Mesoderm / Q000473:pathology; D008928:Mitochondria / Q000473:pathology; D009153:Mutagens / Q000633:toxicity*; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis
D034341:Aristolochic Acids; D018932:Chemokine CCL2; D019394:Ki-67 Antigen; D009153:Mutagens; D003094:Collagen; C000228:aristolochic acid I; C511169:DDR1 protein, rat; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases