Journal Article

A Correlation between a Proteomic Evaluation and Conventional Measurements in the Assessment of Renal Proximal Tubular Toxicity

Lasantha R. Bandara, Mike D. Kelly, Edward A. Lock and Sandy Kennedy

in Toxicological Sciences

Volume 73, issue 1, pages 195-206
Published in print May 2003 | ISSN: 1096-6080
Published online May 2003 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfg068
A Correlation between a Proteomic Evaluation and Conventional Measurements in the Assessment of Renal Proximal Tubular Toxicity

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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.

Keywords: kidney; toxicity; proteomics; biomarker; protein profiling; proteases; inflammation

Journal Article.  8588 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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