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Genetic loci that affect aristolochic acid-induced nephrotoxicity in the mouse

Thomas A Rosenquist1

  • 1Department of Pharmacological Sciences, School of Medicine, State University of New York at Stony Brook, Stony Brook, New York 11794-8651, USA. rosenquist@pharm.stonybrook.edu

American Journal of Physiology. Renal Physiology
|March 25, 2011
PubMed

Insights

Aristolochic acids (AA) cause kidney damage and cancer. Genetic factors influence sensitivity, with a key region on mouse chromosome 4 identified as a major contributor to AA-induced kidney toxicity.

Area of Science:

  • Toxicology
  • Genetics
  • Nephrology

Background:

  • Aristolochic acids (AA) are nephrotoxic and carcinogenic compounds found in traditional herbal medicines.
  • AA exposure is linked to aristolochic acid nephropathy (AAN), Balkan endemic nephropathy (BEN), and urothelial cancer.
  • Genetic predisposition is suspected due to variable individual susceptibility to AA-induced renal insufficiency and cancer.

Purpose of the Study:

  • To identify genetic factors influencing susceptibility to aristolochic acid nephropathy (AAN) using a mouse model.
  • To map quantitative trait loci (QTL) associated with proximal tubule dysfunction following AA exposure.

Main Methods:

  • An F2 mouse population was generated from a cross between AA-resistant (C57BL/6J) and AA-sensitive (DBA/2J) strains.
  • Quantitative trait loci (QTL) analysis was performed to identify genetic regions linked to proximal tubule dysfunction after AA administration.

Main Results:

  • A major QTL, termed Aanq1, was identified on chromosome 4.
  • Three additional interacting QTLs (Aanq2-4) were detected.
  • The Aanq1 region showed presence in untreated mice, suggesting pre-existing variations in proximal tubule function.

Conclusions:

  • Genetic factors significantly contribute to aristolochic acid (AA) sensitivity and AAN development.
  • The identified QTLs provide a foundation for elucidating the genetic pathways underlying AA toxicity.
  • Understanding these pathways can improve assessment of human susceptibility to AA in herbal remedies.

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