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Toxicologic Pathology, Vol. 35, No. 4, 521-532 (2007)
DOI: 10.1080/01926230701338933
© 2007 Society of Toxicologic Pathology

Articles

Clinicopathological and Tissue Indicators of Para-Aminophenol Nephrotoxicity in Sprague–Dawley Rats

Amy Yang1, Dusko Trajkovic2, Oscar Illanes3 and Fernando Ramiro-Ibáñez4

2 World Wide Safety Sciences, Pfizer Global Research and Development, San Diego, California 92121, USA

Correspondence: Address correspondence to: Fernando Ramiro-Ibáñez, IDEXX Laboratories Ltd., Grange House, Sandbeck Way, Wetherby, West Yorkshire, LS22 7DN, UK; e-mail:kumiro46{at}hotmail.com

A model of para-aminophenol (PAP) nephrotoxicity in Sprague–Dawley rats was utilized to characterize potential indicators of toxicity in the kidney and in biofluids, and to chronicle the progression of acute renal injury. Rats were administered PAP at a low or high dose and examined terminally at 6, 24 and 48 hours (4 animals/group with matching controls). Acute tubular necrosis was observed in the medullary rays (low and high doses) and the outer stripe of outer medulla (high dose only) as early as 6 hours postdosing. Starting at 24 hours, regeneration of the tubular epithelium was evident in both low and high dose studies. Associated with the tubular lesions, we observed elevation of urinary {alpha}-glutathione S-transferase levels, an indicator of proximal tubular injury. By immunohistochemistry of the kidney, decreased {gamma}-glutamylcysteine synthetase expression correlated with tubular injury, especially at high dose, whereas elevation of vimentin, osteopontin, and Ki-67 expression was concurrent with tubular regeneration. Clusterin and kidney injury molecule-1 displayed expression patterns characteristic of both renal injury and regeneration. Taken together, this study provided insight into the progression of nephrotoxicity, and allowed the evaluation of potential urinary and tissue protein biomarkers that could complement the early detection of acute tubular injury.

Key Words: Nephrotoxicity • p-aminophenol • immunohistochemistry • {alpha}-glutathione S-transferase • clusterin • KIM-1 • osteopontin

Abbreviations: ATN, acute tubular necrosis • BUN, blood urea nitrogen • GCS, {gamma}-glutamylcysteine synthetase • GGT, {gamma}-glutamyl transpeptidase • GST, glutathione S-transferase • H&E, hematoxylin and eosin • IHC, immunohistochemistry • ISOM, inner stripe of the outer medulla • KIM-1, kidney injury molecule-1 • MR, medullary ray • NAG, N-acetyl-β-D-glucosaminidase • OSOM, outer stripe of the outer medulla • PAP, para-aminophenol • PAS, periodic acid-Schiff • PST, proximal straight tubule


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