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Table 1 Hallmarks and causes defining AKI

From: 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

Event

Modulated associated event

Modulation in AKI

Molecular cause

RAAS activation

Angiotensin signalling

up

Cathepsin/kallikrein/kininogen activity, blood pressure, pH

Vasoconstriction

Vasoconstrictors (endothelin, angiotensin, MMP2)

up

RAAS pathway induction, endothelial obstruction

Ā 

Vasodilators (NO)

down

NOS inhibition, reduced NO bioavailability by ROS activity

Hyperglycaemia

Ā 

up

20-hydroxyeicosatetraenoic acid (20-HETE), Glycogen phosphorylase, PPARĪ³

Elevated blood pressure

Hypertension

up

Renin, 20-hydroxyeicosatetraenoic acid (20-HETE), mineralocorticoid receptor

Hypoxia

HIF1Ī±

up

Induction by vasoconstriction and ECM accumulation

Ā 

NADPH oxidases

up

Induction by RAAS and PLCĪ²

Ā 

ROS levels

up

NAD(P)H oxidases, P450 isoforms, Xanthine dehydrogenase

Ā 

NFĪŗB activity

up

ROS-modulated activation

Ā 

Inflammation factors (TNFĪ±, TF, PAT1, MCP1)

up

NFĪŗB-mediated gene expression

Ā 

Inflammation and inflammatory response

up

JAK/STAT- and NFĪŗB-dependent gene activation, other pathways

Ā 

Atherogenesis, fibrinogenesis

up

TGFĪ² signalling and gene activation pathway

Ā 

ATP levels

down

Depletion by PMCA activity and others, and inhibition of de-novo ATP production

Ā 

NAD levels

down

Rundown by PARP

Ā 

Hypoxanthine levels

up

Metabolic shift from accumulated XMP, IMP and Inosine

Ā 

Necrosis

up

ROS, SOD, OH., DNA damage, PARP, NAD rundown

PI3K modulation

PI3Kinase activity

down

Inhibition by Jnk and PKCĪ±

Ā 

Insulin signalling

down

Inhibition by RAAS and PPARĪ³ systems

Accumulation of free and esterified cholesterol

Systemic stress response

up

LIPE inhibition by PP1

Na+/Cl- retention, increased luminal Na+

Aldosterone/cortisol signalling events

up

Mineralocorticoid/Glucocorticoid-receptors, acting on Na+/Cl- pumps

Ras activation

Ras signalling

up

Mineralocorticoid/Glucocorticoid-receptor-dependent gene activation, Angiotensin receptor signalling

Cytoskeletal reorganization

ECM remodelling

up

Hsp27, ATP depletion, Rac1 activation, Ras mediated events

Tubular cell dynamics

Infiltration of immature cells

up

Pro-apoptotic signals

  1. Clinical and disease model observations were analysed based on modulated associated events, directionality in terms of in- or decrease, and plausible molecular causes.