A combinatorial approach of proteomics and systems biology in unravelling the mechanisms of acute kidney injury (AKI): Involvement of NMDA receptor GRIN1 in murine AKI
Entity
UAM. Departamento de MedicinaDate
2013-10-30Citation
10.1186/1752-0509-7-110
BMC Systems Biology 7.110 (2013)
ISSN
1752-0509DOI
10.1186/1752-0509-7-110Funded by
Grant support: FEDER funds FIS ISCIII-RETIC REDinREN (RD12/0021 and PS09/00447), Comunidad de Madrid (CIFRA S2010/BMD-2378). Salary support: FIS-Sara Borrell to MDSN, Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laín-Entralgo/CM) to AO.Project
Comunidad de Madrid. S2010/BMD-2378/CIFRAEditor's Version
http://dx.doi.org/10.1186/1752-0509-7-110; http://www.biomedcentral.com/1752-0509/7/110Subjects
Acute kidney injury; NMDA receptor; Pathways; Proteomics; Systems biology; MedicinaRights
© 2013 Husi et al.Abstract
Background
Acute kidney injury (AKI) is a frequent condition in hospitalised patients undergoing major surgery or the critically ill and is associated with increased mortality. Based on the volume of the published literature addressing this condition, reporting both supporting as well as conflicting molecular evidence, it is apparent that a comprehensive analysis strategy is required to understand and fully delineate molecular events and pathways which can be used to describe disease induction and progression as well as lead to a more targeted approach in intervention therapies.
Results
We used a Systems Biology approach coupled with a de-novo high-resolution proteomic analysis of kidney cortex samples from a mouse model of folic acid-induced AKI (12 animals in total) and show comprehensive mapping of signalling cascades, gene activation events and metabolite interference by mapping high-resolution proteomic datasets onto a de-novo hypothesis-free dataspace. The findings support the involvement of the glutamatergic signalling system in AKI, induced by over-activation of the N-methyl-D-aspartate (NMDA)-receptor leading to apoptosis and necrosis by Ca2+-influx, calpain and caspase activation, and co-occurring reactive oxygen species (ROS) production to DNA fragmentation and NAD-rundown. The specific over-activation of the NMDA receptor may be triggered by the p53-induced protein kinase Dapk1, which is a known non-reversible cell death inducer in a neurological context. The pathway mapping is consistent with the involvement of the Renin-Angiotensin Aldosterone System (RAAS), corticoid and TNFα signalling, leading to ROS production and gene activation through NFκB, PPARγ, SMAD and HIF1α trans-activation, as well as p53 signalling cascade activation. Key elements of the RAAS-glutamatergic axis were assembled as a novel hypothetical pathway and validated by immunohistochemistry.
Conclusions
This study shows to our knowledge for the first time in a molecular signal transduction pathway map how AKI is induced, progresses through specific signalling cascades that may lead to end-effects such as apoptosis and necrosis by uncoupling of the NMDA receptor. Our results can potentially pave the way for a targeted pharmacological intervention in disease progression or induction.
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Google Scholar:Husi, Holger
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Sánchez Niño, María Dolores
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Delles, Christian
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Mullen, William
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Vlahou, Antonia
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Ortiz Arduán, Alberto
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Mischak, Harald
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