Probenecid prevents acute tubular necrosis in a mouse model of aristolochic acid nephropathy

Kidney Int. 2012 Nov;82(10):1105-13. doi: 10.1038/ki.2012.264. Epub 2012 Aug 1.


Experimental aristolochic acid nephropathy is characterized by early tubulointerstitial injury followed by fibrosis, reproducing chronic lesions seen in humans. In vitro, probenecid inhibits aristolochic acid entry through organic anion transporters, reduces specific aristolochic acid-DNA adduct formation, and preserves cellular viability. To test this in vivo, we used a mouse model of aristolochic acid nephropathy displaying severe tubulointerstitial injuries consisting of proximal tubular epithelial cell necrosis associated to transient acute kidney injury followed by mononuclear cell infiltration, tubular atrophy, and interstitial fibrosis. Treatment with probenecid prevented increased plasma creatinine and tubulointerstitial injuries, and reduced both the extent and the severity of ultrastructural lesions induced by aristolochic acid, such as the loss of brush border, mitochondrial edema, and the disappearance of mitochondrial crests. Further, the number of proliferating cell nuclear antigen-positive cells and total aristolochic acid-DNA adducts were significantly reduced in mice receiving aristolochic acid plus probenecid compared with mice treated with aristolochic acid alone. Thus, we establish the nephroprotective effect of probenecid, an inhibitor of organic acid transporters, in vivo toward acute proximal tubular epithelial cell toxicity in a mouse model of aristolochic acid nephropathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aristolochic Acids*
  • Atrophy
  • Biomarkers / blood
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Creatinine / blood
  • Cytoprotection
  • DNA Adducts / metabolism
  • Disease Models, Animal
  • Fibrosis
  • Kidney Tubular Necrosis, Acute / blood
  • Kidney Tubular Necrosis, Acute / chemically induced
  • Kidney Tubular Necrosis, Acute / pathology
  • Kidney Tubular Necrosis, Acute / prevention & control*
  • Kidney Tubules / drug effects*
  • Kidney Tubules / metabolism
  • Kidney Tubules / ultrastructure
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nephritis, Interstitial / blood
  • Nephritis, Interstitial / chemically induced
  • Nephritis, Interstitial / pathology
  • Nephritis, Interstitial / prevention & control*
  • Organic Anion Transporters / antagonists & inhibitors
  • Organic Anion Transporters / metabolism
  • Probenecid / pharmacology*
  • Proliferating Cell Nuclear Antigen / metabolism
  • Protective Agents / pharmacology*
  • Time Factors


  • Aristolochic Acids
  • Biomarkers
  • DNA Adducts
  • Organic Anion Transporters
  • Proliferating Cell Nuclear Antigen
  • Protective Agents
  • aristolochic acid I
  • Creatinine
  • Probenecid