The counter regulatory axis of the renin angiotensin system in the brain and ischaemic stroke: Insight from preclinical stroke studies and therapeutic potential

Figures

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  Fig. 1. The classical renin angiotensin system. The protein angiotensinogen is constitutively released from the liver into the circulation [22]. In response to detection of reduced BP, reduced electrolytes or sympathetic innervation in the kidney [23], the enzyme renin is secreted from the kidney (red) which cleaves angiotensinogen to the decapeptide angiotensin I (Ang I). Angiotensin converting enzyme (ACE) is present on the endothelial wall of blood vessels in particular in the lung [24,25]. ACE cleaves Ang I to the octapeptide Ang II, which acts upon the angiotensin II type 1 receptor (AT1R) to increase BP and blood volume by vasoconstriction of blood vessel [26], stimulating aldosterone release from the adrenal gland (on top of the kidney) and hence increasing sodium and water uptake [27], and actions on the brain increasing arterial pressure by sympathetic innervation or to increase the thirst response and release vasopressin to increase water uptake [28,29]. ACE inhibitors (ACEi) or angiotensin receptor blockers (ARB) (orange) are BP lowering medications which block these elements of the RAS to prevent increased BP. Letters in peptides indicate the amino acid sequence. (For…

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  Fig. 2. The extended RAS and counter-regulatory axis. Diagram illustrating the additional discoveries in the RAS. Prorenin is constitutively secreted from the kidney (black block arrow) while cleaved renin is secreted in response to stimuli (red block arrow) [31]. Renin acts directly on angiotensinogen to cleave it to Ang I, while both prorenin and renin can bind to the (pro)renin receptor (PRR) allowing increased cleavage activity of angiotensinogen [32]. The classic and counter-regulatory enzymes for angiotensin peptide cleavage, angiotensin converting enzyme (ACE) (grey) [33] and ACE2 (green) [34] are shown along with additional enzymes which result in peptide cleavage (black) [[35], [36], [37], [38], [39], [40], [41], [42], [43], [44]]. Dashed lines represent cleavage while coloured arrows indicate action of the peptide upon the colour coded receptors. Ang-(1–5), Ang III, Ang IV, Ang-(1–7) and Ang-(1–9) are all active peptides in the RAS [[45], [46], [47], [48], [49]]. Ang A shows a reduced vasoconstrictive effect through AT1R compared to Ang II and also acts upon the AT2R [50]. The angiotensin II type 2 receptor (AT2R), Mas receptor and Mas related GPCR type D (MrgD) receptor form…

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  Fig. 3. AT1R signalling. Diagram depicting summary of intracellular signalling cascades induced by angiotensin II type 1 receptor (AT1R) activation by Ang II, or blocked by angiotensin receptor blockers (ARBs) or heterodimerisation with angiotensin II type 2 receptor (AT2R) or Mas receptor. Arrows indicate activation while dashed line arrows indicate production or cleavage to form a product. Signalling information obtained from [16,51,[121], [122], [123],52,107,[115], [116], [117], [118], [119], [120]]. Abbreviations: AA mets, arachidonic acid metabolites; AA, arachidonic acid; ASK1, apoptosis signal regulating kinase 1; DAG, diacylglycerol; ERK 1/2, extracellular signal related kinase 1/2; FAK, focal adhesion kinase; IP3, inositol trisphosphate; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; MAPKs, mitogen activated protein kinases; NOX, NAD(P)H oxidases; nNOS; neuronal nitric oxide synthacse; NRTKs, non-receptor tyrosine kinases; p38, p38 MAPK; PA, phosphatidic acid; PC, phosphatidylcholine; PDGFR, platelet derived growth factor receptor; PIP2, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLA2, phospholipase A2; PLC, phospholipase C; PLD, phospholipase D; ROS,…

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  Fig. 4. Mas receptor signalling. Diagram depicting summary of intracellular signalling cascades induced by Mas receptor (Mas receptor) activation. Agonists and antagonists are also shown along with receptors with which functional heterodimerisation can occur (AT2R and the bradykinin 2 receptor (B2R)). Arrows indicate activation while dashed line arrows indicate production or cleavage to form a product. Signalling information obtained from [127,131,166,167,[132], [133], [134],137,140,156,164,165]. Abbreviations: AA mets, arachidonic acid metabolites; AA, arachidonic acid; Akt, protein kinase B; cGMP, cyclic guanidine monophosphate; eNOS, endothelial nitric oxide synthase; MAPKs, mitogen activated protein kinases; NO, nitric oxide; PI3K, phosphoinositide-3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PKA: protein kinase A; PLA2, phospholipase A2; SHP-2, SH2 domain-containing protein tyrosine phosphatase-2.

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  Fig. 5. AT2R signalling. Diagram depicting summary of intracellular signalling cascades induced by angiotensin II type 2 receptor (AT2R) activation. Agonists and antagonists are also shown along with receptors with which functional heterodimerisation or homodimerization can occur. Arrows indicate activation while dashed line arrows indicate production or cleavage to form a product. Signalling information obtained from [53,100,219,[221], [222], [223], [224], [225], [226], [227],128,174,186,187,[203], [204], [205], [206]]. Abbreviations: AA mets, arachidonic acid metabolites; AA, arachidonic acid; Bcl-2, B-cell lymphoma 2; cGMP, cyclic guanidine monophosphate; eNOS, endothelial nitric oxide synthase; JNK; c-Jun N-terminal kinase; MAPKs, mitogen activated protein kinases; MKP-1, MAPK phosphatase-1; NO, nitric oxide; PLA2, phospholipase A2; PP2A, protein phosphatase 2A; SHP-1, Src homology region 2 domain-containing phosphatase.