Characterization of renal papillary antigen 1 (RPA-1), a biomarker of renal papillary necrosis.
Renal papillary necrosis (RPN) is a relatively common toxicity observed in preclinical drug safety testing. It is also observed in a variety of human diseases. RPN is difficult to diagnose without expensive scanning methods or histopathology. A noninvasive biomarker that could be detected at early stages of kidney damage would be of great value both to preclinical drug safety testing and in the clinic. An antibody raised to an unknown epitope of an antigen in rat kidney papilla was found to be specific for collecting duct cells in the kidney; this was termed renal papillary antigen 1 (RPA-1). In this study, the authors show that RPA-1 is an early biomarker of RPN in two different rat models of toxicity: 2-bromoethanamine (BEA) and N-phenylanthranilic acid (NPAA). RPA-1 can be detected in urine at early stages of toxicity and correlates well with the histopathology observed. We also characterized the biochemical properties of RPA-1 and found that the antigen is a high molecular weight membrane bound glycoprotein, with the epitope likely to be carried on an N-linked carbohydrate structure. This study demonstrates that RPA-1 is an excellent marker of RPN that can be used to detect this toxicity in preclinical safety testing.
Price
Sally A
SA
Safety Assessment, AstraZeneca UK Ltd, Macclesfield, Cheshire SK10 4TG, UK. sally.a.price@astrazeneca.com
Davies
Dai
D
Rowlinson
Rachel
R
Copley
Clive G
CG
Roche
Andrew
A
Falkenberg
Frank W
FW
Riccardi
Daniela
D
Betton
Graham R
GR
D000818:Animals; D000941:Antigens / Q000032:analysis* / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis*; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005021:Ethylamines / Q000633:toxicity; D054361:Fenamates / Q000633:toxicity; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007679:Kidney Medulla / Q000276:immunology / Q000378:metabolism*; D007681:Kidney Papillary Necrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D000941:Antigens; D015415:Biomarkers; D005021:Ethylamines; D054361:Fenamates; C004504:2-bromoethylamine