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

BMC Systems Biology

Harald Mischak³  Alberto Ortiz¹  Antonia Vlahou⁵  William Mullen⁴  Christian Delles⁴  Maria Dolores Sanchez-Niño²  Holger Husi⁴ 

[1] IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid and Fundación Renal Iñigo Alvarez de Toledo-IRSIN, 28003 Madrid, Spain;REDINREN, 28040 Madrid, Spain;Mosaiques diagnostics GmbH, 30625 Hannover, Germany;BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA,, UK;Biomedical Research Foundation,, cademy of Athens, 4 Soranou Ephessiou, 115 27 Athens, Greece

关键词: Systems biology;    Proteomics;    Pathways;    NMDA receptor;    Acute kidney injury;   

Others  :  1141969
DOI  :  10.1186/1752-0509-7-110

 received in 2013-07-02, accepted in 2013-10-28,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Husi et al.; licensee BioMed Central Ltd.

【 图 表 】

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