Positive Feedback Mechanism in Aristolochic Acid I Exposure-Induced Anemia and DNA Adduct Formation: Implications for Balkan Endemic Nephropathy

J Agric Food Chem. 2024 Aug 14;72(32):18155-18161. doi: 10.1021/acs.jafc.4c03508. Epub 2024 Aug 1.

Abstract

Balkan endemic nephropathy (BEN) is a chronic kidney disease that predominantly affects inhabitants of rural farming communities along the Danube River tributaries in the Balkans. Long-standing research has identified dietary exposure to aristolochic acids (AAs) as the principal toxicological cause. This study investigates the pathophysiological role of anemia in BEN, noting its earlier and more severe manifestation in BEN patients compared to those with other chronic kidney diseases. Utilizing a mouse model, our research demonstrates that prolonged exposure to aristolochic acid I (AA-I) (the most prevalent AA variant) leads to significant red blood cell depletion through DNA damage, such as DNA adduct formation in bone marrow, prior to observable kidney function decline. Furthermore, in vitro experiments with kidney cells exposed to lowered oxygen and pH conditions mimicking an anemia environment show enhanced DNA adduct formation, suggesting increased AA-I mutagenicity and carcinogenicity. These findings indicate for the first time a positive feedback mechanism of AA-induced anemia, DNA damage, and kidney impairment in BEN progression. These results not only advance our understanding of the underlying mechanisms of BEN but also highlight anemia as a potential target for early BEN diagnosis and therapy.

Keywords: Balkan endemic nephropathy; DNA adduct; anemia; aristolochic acids; dietary exposure.

MeSH terms

  • Anemia* / chemically induced
  • Anemia* / genetics
  • Anemia* / metabolism
  • Animals
  • Aristolochic Acids* / adverse effects
  • Aristolochic Acids* / toxicity
  • Balkan Nephropathy* / chemically induced
  • Balkan Nephropathy* / genetics
  • Balkan Nephropathy* / metabolism
  • DNA Adducts* / metabolism
  • DNA Damage / drug effects
  • Female
  • Humans
  • Kidney / drug effects
  • Kidney / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL

Substances

  • Aristolochic Acids
  • DNA Adducts
  • aristolochic acid I