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A potential biomarker of kidney damage identified by proteomics: preliminary findings
Lasantha R Bandara1, Mike D Kelly, Edward A Lock
1Oxford GlycoSciences (UK) Ltd, The Forum, 86 Milton Park, Abingdon, Oxon, OX14 4RY, UK. lan.bandara@ogs.co.uk
Abstract:
4-Aminophenol (4-AP) and D-serine are established rodent nephrotoxins that selectively damage renal proximal tubules. In an attempt to understand the mechanism of action of these toxicants in greater detail, a high throughput proteomics approach was used to profile protein changes in the plasma of animals treated with these compounds. Male Fischer 344 and Alderley Park rats were treated with increasing doses of 4-AP or D-serine and plasma samples were collected over time. Control groups received either saline or the non-toxic enantiomer, L-serine. Using high throughput two-dimensional gel analysis, a number of plasma proteins showing dose- and time-dependent regulation were identified. One toxicity-associated plasma protein was identified as the cellular enzyme fumarylacetoacetate hydrolase (FAH), which is known to be required for tyrosine metabolism. The FAH gene is mutated in the human genetic disorder type I tyrosinaemia, which is associated with liver and kidney abnormalities and neurological disorders. FAH was elevated in the plasma of animals treated with 4-AP and D-serine at early time points and returned to baseline levels after 3 weeks. The protein was not elevated in the plasma of control animals or those treated with L-serine. The presence of FAH in plasma is intriguing as it is normally a cellular enzyme with no known function in plasma. It is possible that 4-AP and D-serine may work through a previously unknown mechanism in the kidney via regulation of tyrosine metabolism or FAH activity. Therefore, FAH may function in a fashion analogous to the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzymes that are used to measure liver injury. The link between kidney toxicants and inherited tyrosinaemia also raises the possibility that FAH may be a marker of kidney toxicity in humans. These observations highlight the value of proteomics in identifying new biomarkers and providing new unprecedented insights into complex biological mechanisms.
Insights
4-Aminophenol and D-serine, kidney toxicants, increase plasma fumarylacetoacetate hydrolase (FAH) in rats. This suggests FAH may be a novel biomarker for kidney toxicity and offers insights into tyrosine metabolism disruption.
Area of Science:
- Proteomics
- Toxicology
- Biochemistry
Background:
- 4-Aminophenol (4-AP) and D-serine are known rodent nephrotoxins targeting renal proximal tubules.
- Understanding the precise mechanism of action for these toxicants is crucial for developing effective countermeasures.
Purpose of the Study:
- To investigate the molecular mechanisms underlying 4-AP and D-serine induced nephrotoxicity using a high-throughput proteomics approach.
- To identify novel plasma protein biomarkers associated with kidney damage caused by these toxicants.
Main Methods:
- Male Fischer 344 and Alderley Park rats were administered varying doses of 4-AP or D-serine over time.
- Plasma samples were analyzed using high-throughput two-dimensional gel electrophoresis.
- Protein expression changes were quantified and identified.
Main Results:
- Several plasma proteins exhibited dose- and time-dependent regulation following toxicant exposure.
- Fumarylacetoacetate hydrolase (FAH), a cellular enzyme involved in tyrosine metabolism, was significantly elevated in plasma.
- FAH levels returned to baseline after 3 weeks and were not altered in control or L-serine treated groups.
Conclusions:
- Elevated plasma FAH in response to 4-AP and D-serine suggests a potential role in nephrotoxicity, possibly via altered tyrosine metabolism.
- FAH may serve as a novel biomarker for kidney toxicity, analogous to liver enzymes AST and ALT.
- Proteomics is a valuable tool for discovering new biomarkers and elucidating complex toxicological mechanisms.