Proximal tubules and podocytes are toxicity targets of bucillamine in a mouse model of drug-induced kidney injury

• Published in: European journal of pharmacology 2011-11, Vol.670 (1), p.208-215
• Main Authors: Fujiwara, Yoko, Tsuchiya, Hiroyoshi, Sakai, Nobuya, Shibata, Katsushi, Fujimura, Akio, Koshimizu, Taka-aki
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - blood; Acute Kidney Injury - chemically induced; Acute Kidney Injury - genetics; Acute Kidney Injury - urine; adverse effects; Animal model; animal models; Animals; Biological and medical sciences; biomarkers; Bucillamine; Cysteine - analogs & derivatives; Cysteine - toxicity; cytochrome P-450; d-Penicillamine; Disease Models, Animal; DNA microarray; drugs; gene expression; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - metabolism; Kidney Tubules, Proximal - pathology; Male; Medical sciences; Mice; Mice, Inbred BALB C; Nephrectomy; Nephrotoxicity; NGAL (Neutrophil gelatinase-associated lipocalin); Oligonucleotide Array Sequence Analysis; oral administration; pathogenesis; patients; Pharmacology. Drug treatments; Podocytes - drug effects; Podocytes - metabolism; Podocytes - pathology; Proteinuria - blood; Proteinuria - chemically induced; Proteinuria - genetics; Proteinuria - urine; proximal tubules; rheumatoid arthritis; subtilisin; Transcriptome - drug effects; Up-Regulation - drug effects; urine
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2011.08.051

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 2000mg/kg/day) or d-penicillamine (2000mg/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.