ToxSci Advance Access originally published online on March 25, 2003
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Toxicological Sciences 73, 195-206 (2003)
Copyright © 2003 by the Society of Toxicology
SYSTEM TOXICOLOGY |
A Correlation between a Proteomic Evaluation and Conventional Measurements in the Assessment of Renal Proximal Tubular Toxicity
* Oxford GlycoSciences (U.K.), Ltd., the Forum, 86 Milton Park, Abingdon, Oxon OX14 4RY, United Kingdom;
Syngenta CTL, Alderley Park, Cheshire, SK10 4TJ, United Kingdom; and
GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 0DP, United Kingdom
ABSTRACT
4-Aminophenol (4-AP), D-serine, and cisplatin are established rodent nephrotoxins that damage proximal tubules within the renal cortex. Using high throughput 2D gel proteomics to profile protein changes in the plasma of compound-treated animals, we identified several markers of kidney toxicity. Male F344 and Alpk rats were treated with increasing doses of 4-AP, D-serine, or cisplatin, and plasma samples were collected over time. Control groups received saline or nontoxic isomers, L-serine, and transplatin. Plasma proteins that displayed dose- and temporal-dependent regulation in each study were further characterized by mass spectrometry to elucidate the protein identity. Several isoforms of the rat-specific T-kininogen protein were identified in each study. T-kininogen was elevated in the plasma of 4-AP-, D-serine-, and cisplatin-treated animals at early time points, returning to baseline levels 3 weeks after treatment. The protein was not elevated in the plasma of control animals or those treated with nontoxic compounds. We propose that T-kininogen may be required to counteract apoptosis in proximal tubular cells in order to minimize tissue damage following a toxic insult. In addition, T-kininogen may be required to stimulate localized inflammation to aid tissue repair. We also identified several isoforms of the inter-alpha inhibitor H4P heavy chain in the 4-AP and D-serine studies. In each case, the protein expression levels in the blood samples paralleled the extent of kidney toxicity, highlighting the correlation between protein alterations and clinical chemistry endpoints. A further set of proteins correlating with kidney damage was found to be a component of the complement cascade and other blood clotting factors, indicating a contribution of the immune system to the observed toxicity. These observations underscore the value of proteomics in identifying new biomarkers and in the elucidation of mechanisms of toxicity.
Key Words: kidney; toxicity; proteomics; biomarker; protein profiling; proteases; inflammation.
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