title: Proximal tubules and podocytes are toxicity targets of bucillamine in a mouse model of drug-induced kidney injury.
abstract: Effective detection of potential nephrotoxicity is crucial for pre-clinical drug development. We evaluated a sensitive animal model for drug-induced kidney injury, which includes hemi-nephrectomy of mice. Although bucillamine and d-penicillamine are used for the treatment of rheumatoid arthritis in Japan, drug-related adverse effects on the kidney can limit their therapeutic utilities. When bucillamine (1000 or 2000 mg/kg/day) or d-penicillamine (2000 mg/kg/day) were orally administered to hemi-nephrectomised BALB/c mice, the urinary protein levels of bucillamine-treated mice, but not of those treated with d-penicillamine, the vehicle, or in bucillamine treated unnephrectomized mice, were significantly increased and remained high during the 4-week drug-loading period. Membranous glomerulonephropathy occasionally seen in bucillamine/d-penicillamine-treated arthritis patients was not reproduced in mice. Instead, our mouse model showed proximal tubular injury and podocyte foot process effacement in the bucillamine-treated kidneys. These two cell types are also the primary targets of the experimental Heymann membranous glomerulonephropathy. Gene expression profiling of the bucillamine-treated mice identified lipocalin 2 as a significantly up-regulated transcript together with cytochrome P450 CYP4a14, a group-specific component, and proprotein convertase subtilisin/kexin type 9. Moreover, large amounts of lipocalin 2 were detected in the urine of the bucillamine-treated mice, but not in the hemi-nephrectomised control mice. These results indicate that hemi-nephrectomy effectively promotes acute kidney injury by bucillamine, which is accompanied by up-regulation of the urinary biomarker lipocalin 2. Our mouse model with initial stage of kidney injury should be useful to analyse the pathogenesis of drug-induced glomerular and tubular injuries.
authors.affiliation: Division of Molecular Pharmacology, Department of Pharmacology, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Tsuchiya
authors.forename: Nobuya
authors.initials: N
authors.lastname: Sakai
authors.forename: Katsushi
authors.initials: K
authors.lastname: Shibata
authors.forename: Akio
authors.initials: A
authors.lastname: Fujimura
authors.forename: Taka-aki
authors.initials: TA
authors.lastname: Koshimizu
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000139:chemically induced* / Q000235:genetics / Q000652:urine; D000818:Animals; D003545:Cysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D004195:Disease Models, Animal; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009392:Nephrectomy; D020411:Oligonucleotide Array Sequence Analysis; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011507:Proteinuria / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000652:urine; D059467:Transcriptome / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D003545:Cysteine; C026535:bucillamine