Biomarkers of collecting duct injury in Han-Wistar and Sprague-Dawley rats treated with N-phenylanthranilic Acid.
N-phenylanthranilic acid is a chloride channel blocker that causes renal papillary necrosis in rats. Studies were conducted in two strains of male rats to evaluate novel biomarkers of nephrotoxicity. Han-Wistar rats were given daily oral doses of 50, 350, or up to 700 mg/kg/day of NPAA, and Sprague-Dawley rats were given 50 or 400 mg/kg/day of NPAA. Rats were euthanized on days 8 and 15. The candidate kidney injury biomarkers renal papillary antigen-1 (RPA-1, for collecting duct injury), clusterin (for general kidney injury), α-glutathione-S-transferase (a proximal tubular marker), and µ-glutathione-S-transferase (a distal tubular marker) were measured in urine by enzyme immunoassay. Characteristic degeneration and necrosis of the collecting duct and renal papilla were observed in Han-Wistar rats at the high dose on day 8 and at the mid and high doses on day 15, and in Sprague-Dawley rats given the high dose on days 8 and 15. Increases in urinary RPA-1, and to a lesser extent urine clusterin, were generally associated with the presence of collecting duct injury and were more sensitive than BUN and serum creatinine. On the other hand, decreases in α-glutathione-S-transferase without proximal tubule lesions in both strains and decreases in µ-glutathione-S-transferase in Sprague-Dawley rats only were not associated with morphological proximal or distal tubule abnormalities, so both were of less utility. It was concluded that RPA-1 is a new biomarker with utility in the detection of collecting duct injury in papillary necrosis in male rats.
AstraZeneca Pharmaceuticals, Macclesfield, Cheshire, UK. grbetton@aol.com
Graham R
GR
Betton
Daniela
D
Ennulat
David
D
Hoffman
Jean-Charles
JC
Gautier
Ernie
E
Harpur
Syril
S
Pettit
D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000097:blood / Q000652:urine; D001806:Blood Urea Nitrogen; D051152:Clusterin / Q000652:urine; D003404:Creatinine / Q000097:blood; D005982:Glutathione Transferase / Q000652:urine; D006651:Histocytochemistry; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced* / Q000473:pathology / Q000652:urine; D007685:Kidney Tubules, Collecting / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009336:Necrosis; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018675:Toxicity Tests; D062367:ortho-Aminobenzoates / Q000633:toxicity*
D015415:Biomarkers; C498500:Clu protein, rat; D051152:Clusterin; D062367:ortho-Aminobenzoates; C001209:fenamic acid; D003404:Creatinine; D005982:Glutathione Transferase