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The occurrence of renal papillary necrosis (RPN), seen only in dogs after repeated oral administration of nefiracetam, a neurotransmission enhancer, at a relatively high dose, is because of inhibition of renal prostaglandin synthesis by the nefiracetam metabolite M-18. In this study, analyses of urinary proteins and renal mRNA expression were performed to investigate the possible existence of a specific protein expressing the characteristics of RPN evoked by nefiracetam. In the sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of urinary proteins from male dogs given nefiracetam at 300 mg kg(-1) day(-1) over weeks 5-11, a protein of approximately 40 kDa, which was not seen in control urine, and protein of approximately 30 kDa emerged as distinct bands. Subsequently, clusterin precursor was identified in the former band and tissue kallikrein precursor in the latter by LC-electrospray ionization tandem mass spectrometry (LC-ESI-MS-MS). By quantitative real-time RT-PCR analysis with renal morphological aspects, individual findings showed that renal clusterin mRNA was increased in dogs with severe renal injury, and renal tissue kallikrein also increased, presumably related to hemodynamics. These results demonstrate that changes in renal clusterin mRNA may reflect the progression or severity of RPN, whereas upregulation of tissue kallikrein mRNA may subsequently play a compensating role in the prevention of RPN.