期刊
KIDNEY INTERNATIONAL
卷 82, 期 10, 页码 1105-1113出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ki.2012.264
关键词
acute tubular necrosis; aristolochic acid nephropathy; DNA adducts; interstitial renal fibrosis; probenecid; proximal tubular epithelial cells
资金
- Cancer Research, UK
- Fonds Erasme pour la Recherche Medicale, Brussels, Belgium
- Cancer Research UK [14329] Funding Source: researchfish
- Medical Research Council [G0801056B] Funding Source: researchfish
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. Kidney International (2012) 82, 1105-1113; doi:10.1038/ki.2012.264; published online 1 August 2012
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