Aristolochic acids induce chronic renal failure with interstitial fibrosis in salt-depleted rats.
Chinese-herb nephropathy (CHN) is a rapidly progressive renal fibrosis associated with the intake of a Chinese herb (Aristolochia fangchi) containing nephrotoxic and carcinogenic aristolochic acids (AA). This study attempted to reproduce the main features of human CHN (renal failure, tubular atrophy, and interstitial fibrosis) in a rat model similar to that of cyclosporin-induced nephropathy. Salt-depleted male Wistar rats received daily subcutaneous injections of either 1 mg/kg body wt AA (low-dose AA group), 10 mg/kg body wt AA (high-dose AA group), or vehicle (control group) for 35 d. On days 10 and 35, assessment of renal function, measurements of urinary excretion of glucose, protein, and leucine aminopeptidase, and histologic analyses were performed (six rats euthanized/group). High-dose AA induced glucosuria, proteinuria, and elevated serum creatinine levels and reduced leucine aminopeptidase enzymuria on days 10 and 35, whereas low-dose AA had no significant effect. Tubular necrosis associated with lymphocytic infiltrates (day 10) and tubular atrophy surrounded by interstitial fibrosis (day 35) were the histologic findings for the high-dose AA-treated rats. In both AA groups, urothelial dysplasia was also observed, as well as fibrohistiocytic sarcoma at the injection site. A short-term model of AA-induced renal fibrosis was established in salt-depleted Wistar rats. These results support the role of AA in human CHN and provide a useful model for examination of the pathophysiologic pathways of renal fibrosis.
Debelle
Frédéric D
FD
*Laboratory for Research on Peptide Metabolism, Faculty of Medicine, and Departments of Nephrology and Pathology, Erasme Hospital, Université LIbre de Bruxelles, Brussels, Belgium.
Nortier
Joëlle L
JL
*Laboratory for Research on Peptide Metabolism, Faculty of Medicine, and Departments of Nephrology and Pathology, Erasme Hospital, Université LIbre de Bruxelles, Brussels, Belgium.
De Prez
Eric G
EG
*Laboratory for Research on Peptide Metabolism, Faculty of Medicine, and Departments of Nephrology and Pathology, Erasme Hospital, Université LIbre de Bruxelles, Brussels, Belgium.
Garbar
Christian H
CH
*Laboratory for Research on Peptide Metabolism, Faculty of Medicine, and Departments of Nephrology and Pathology, Erasme Hospital, Université LIbre de Bruxelles, Brussels, Belgium.
Vienne
Anne R
AR
*Laboratory for Research on Peptide Metabolism, Faculty of Medicine, and Departments of Nephrology and Pathology, Erasme Hospital, Université LIbre de Bruxelles, Brussels, Belgium.
Salmon
Isabelle J
IJ
*Laboratory for Research on Peptide Metabolism, Faculty of Medicine, and Departments of Nephrology and Pathology, Erasme Hospital, Université LIbre de Bruxelles, Brussels, Belgium.
Deschodt-Lanckman
Monique M
MM
*Laboratory for Research on Peptide Metabolism, Faculty of Medicine, and Departments of Nephrology and Pathology, Erasme Hospital, Université LIbre de Bruxelles, Brussels, Belgium.
Vanherweghem
Jean-Louis
JL
*Laboratory for Research on Peptide Metabolism, Faculty of Medicine, and Departments of Nephrology and Pathology, Erasme Hospital, Université LIbre de Bruxelles, Brussels, Belgium.
D000818:Animals; D034341:Aristolochic Acids; D001835:Body Weight; D002295:Carcinoma, Transitional Cell / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage; D005355:Fibrosis; D007279:Injections, Subcutaneous / Q000009:adverse effects; D007668:Kidney / Q000473:pathology* / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000139:chemically induced* / Q000473:pathology* / Q000503:physiopathology; D007684:Kidney Tubules / Q000473:pathology; D008297:Male; D010386:Pelvic Neoplasms / Q000139:chemically induced; D010616:Phenanthrenes / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D012509:Sarcoma / Q000139:chemically induced; D012965:Sodium Chloride / Q000378:metabolism*; D016019:Survival Analysis
D034341:Aristolochic Acids; D004365:Drugs, Chinese Herbal; D010616:Phenanthrenes; D012965:Sodium Chloride; C000228:aristolochic acid I