ABSTRACT
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.
Subject(s)
Antigens/analysis , Biomarkers/analysis , Kidney Medulla/metabolism , Kidney Papillary Necrosis/metabolism , Animals , Antigens/metabolism , Blotting, Western , Enzyme-Linked Immunosorbent Assay , Ethylamines/toxicity , Fenamates/toxicity , Immunohistochemistry , Immunoprecipitation , Kidney Medulla/immunology , Kidney Papillary Necrosis/chemically induced , Kidney Papillary Necrosis/pathology , Male , Rats , Rats, WistarABSTRACT
A series of fenamate quinazolinyl analogues, viz acids 6a-d, esters 6e-h, carbohydrazides 7a-d, arylidenes 8a-d, oxadiazol-2-ones 13a-d and oxadiazol-2-thiones 14a-d, have been prepared and screened for their analgesic (acetic acid-induced writhing), anti-inflammatory (carrageenan-induced rat paw edema) activities as well as their ulcerogenic effects. All the final compounds except 7a-d and 8a-d showed good dual activities. Compounds 6a, 6b, 6e, 6f, 13a and 14a showed activities comparable to that of mefenamic acid (CAS 61-68-7) in the acetic acid-induced writhing model as well as in the carrageenan-induced rat paw edema test at a dose level of 100 mg/ kg.Compounds 6a and 6b were highly ulcerogenic, while compounds 6e, 6f, 13a and 14a exhibited the lowest ulcerogenic effects.
