Abstract
BackgroundAcute 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.ResultsWe 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.ConclusionsThis 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.
Highlights
Acute kidney injury (AKI) is a frequent condition in hospitalised patients undergoing major surgery or the critically ill and is associated with increased mortality
Statistical testing using Mann–Whitney showed that 2521 proteins were statistically significant (p-values
The same approach was used to map the metabolic pathways modulated in AKI, as well as probable gene activation cascades based on reported modulation of transcription factors such as NFκB, which were integrated into the AKI model
Summary
Acute kidney injury (AKI) is a frequent condition in hospitalised patients undergoing major surgery or the critically ill and is associated with increased mortality. In light of the economic burden of 0.4% to 0.6% of the total healthcare costs, corresponding to £400 m - £600 m, annually spent on treatment for acute kidney injury in the UK alone [4], a clear need for development of means to predict and/or early detect and prevent/treat AKI arises. It has been widely accepted that AKI represents a continuum or spectrum of diseases that could be identified at an early stage, rather than the previous terminology of acute renal failure describing an “all or nothing” condition [5]. The recognition of renal impairment at an early stage would allow for an immediate course of action to alleviate symptoms and disrupt the process of functional decline [6], this implies that this condition is comprehensively understood on a molecular level to allow for targeted intervention therapies
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