Aristolochic acids induce chronic renal failure with interstitial fibrosis in salt-depleted rats

J Am Soc Nephrol. 2002 Feb;13(2):431-6.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aristolochic Acids*
  • Body Weight
  • Carcinoma, Transitional Cell / chemically induced
  • Dose-Response Relationship, Drug
  • Drugs, Chinese Herbal* / administration & dosage
  • Fibrosis
  • Injections, Subcutaneous / adverse effects
  • Kidney / pathology*
  • Kidney / physiopathology
  • Kidney Failure, Chronic / chemically induced*
  • Kidney Failure, Chronic / pathology*
  • Kidney Failure, Chronic / physiopathology
  • Kidney Tubules / pathology
  • Male
  • Pelvic Neoplasms / chemically induced
  • Phenanthrenes* / administration & dosage
  • Rats
  • Rats, Wistar
  • Reference Values
  • Sarcoma / chemically induced
  • Sodium Chloride / metabolism*
  • Survival Analysis

Substances

  • Aristolochic Acids
  • Drugs, Chinese Herbal
  • Phenanthrenes
  • Sodium Chloride
  • aristolochic acid I