Betton Graham R, Ennulat Daniela, Hoffman David, Gautier Jean-Charles, Harpur Ernie, Pettit Syril
AstraZeneca Pharmaceuticals, Macclesfield, Cheshire, UK.
Toxicol Pathol. 2012 Jun;40(4):682-94. doi: 10.1177/0192623311436174. Epub 2012 Feb 1.
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.
N-苯基邻氨基苯甲酸是一种氯离子通道阻滞剂，可导致大鼠肾乳头坏死。在两种雄性大鼠品系中进行了研究，以评估肾毒性的新型生物标志物。给Han-Wistar大鼠每日口服剂量为50、350或高达700 mg/kg/天的N-苯基邻氨基苯甲酸，给Sprague-Dawley大鼠每日口服剂量为50或400 mg/kg/天的N-苯基邻氨基苯甲酸。在第8天和第15天对大鼠实施安乐死。通过酶免疫测定法测量尿液中候选肾损伤生物标志物肾乳头抗原-1（RPA-1，用于集合管损伤）、簇集素（用于一般肾损伤）、α-谷胱甘肽-S-转移酶（近端小管标志物）和μ-谷胱甘肽-S-转移酶（远端小管标志物）。在第8天高剂量组以及第15天中、高剂量组的Han-Wistar大鼠中，以及在第8天和第15天高剂量组的Sprague-Dawley大鼠中，观察到集合管和肾乳头的特征性变性和坏死。尿RPA-1升高，尿簇集素升高程度较小，通常与集合管损伤有关，并且比血尿素氮和血清肌酐更敏感。另一方面，两种品系中α-谷胱甘肽-S-转移酶降低但无近端小管病变，以及仅Sprague-Dawley大鼠中μ-谷胱甘肽-S-转移酶降低，均与近端或远端小管形态学异常无关，因此两者的实用性较小。得出的结论是，RPA-1是一种新型生物标志物，可用于检测雄性大鼠乳头坏死中集合管损伤。
