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AT(2) receptor and tissue injury: therapeutic implications - PubMed

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AT(2) receptor and tissue injury: therapeutic implications

Pawel Namsolleck et al. Curr Hypertens Rep. 2014 Feb.

Abstract

The renin-angiotensin system (RAS) plays an important role in the initiation and progression of tissue injuries in the cardiovascular and nervous systems. The detrimental actions of the AT1 receptor (AT1R) in hypertension and vascular injury, myocardial infarction and brain ischemia are well established. In the past twenty years, protective actions of the RAS, not only in the cardiovascular, but also in the nervous system, have been demonstrated. The so-called protective arm of the RAS includes AT2-receptors and Mas receptors (AT2R and MasR) and is characterized by effects different from and often opposing those of the AT1R. These include anti-inflammation, anti-fibrosis, anti-apoptosis and neuroregeneration that can counterbalance pathological processes and enable recovery from disease. The recent development of novel, small-molecule AT2R agonists offers a therapeutic potential in humans with a variety of clinical indications.

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Conflict of interest statement

Pawel Namsolleck, Chiara Recarti, Sébastien Foulquier, and Thomas Unger declare that they have no conflict of interest.

Ulrike Muscha Steckelings has received modest research support (short term fellowship; free supply with drug) from Vicore Pharma.

Figures

Fig. 1
Fig. 1

AT2R-mediated molecular pathways involved in tissue injury. The AT2R can be stimulated either by endogenous ligand Ang II or by exogenous agonists (CGP42112 or C21) resulting in activation or inhibition of multiple molecular pathways. This in turn leads to multiple cellular responses (grey boxes) including anti-inflammation, anti-fibrosis, modulation of apoptosis and enhanced neurite outgrowth. The MAPK-pathway and NFκB-pathway play central roles in the AT2R-mediated responses. Some of the molecular pathways are initiated indirectly via cross-talk with other receptors including Fas, TrkA and TrkB receptors by activation of the receptor or upregulation of ligand expression (e.g., FasL or BDNF). All pathways can be inhibited by the AT2R antagonist, PD123319, or by knocking-down the AT2R (not shown on the graph). Please notice that the edges in the pathway have undirected character (i.e., can represent either activation or inhibition). *growth factors are necessary for p85αPI3K activation. Abbreviations: AT 2R angiotensin AT2 receptor; Ang II angiotensin II; C21 compound 21 (non-peptide AT2R agonist); CGP42112 peptide AT2R agonist; PD123319 non-peptide AT2R antagonist; Trk tyrosine kinase receptor; BDNF brain-derived neurotrophic factor; Fas Fas cell surface death receptor; FasL Fas ligand; CYP2C/2J isoform of arachidonic acid-metabolizing cytochrome P450 enzyme; EET 11,12-epoxyeicosatrienoic acid; NFκB nuclear factor NF-kappa-B; TIMP tissue inhibitor of metalloproteinases; MMPs matrix metalloproteinases; PKCα protein kinase C, alpha; p21 RAS Ras family of small GTP binding proteins; ATIP/ATBP AT2 receptor-interacting protein (or AT2 receptor binding protein); SHP-1 protein-tyrosine phosphatase SHP-1; MMS2 methyl methanesulfonate sensitive 2; nNOS neuronal nitric oxide synthase; NO nitric oxide; cGMP cyclic guanosine monophosphate; PKG cGMP-dependent protein kinase; NADPH reduced form of nicotinamide adenine dinucleotide phosphate; ROS reactive oxygen species; MEK mitogen-activated protein kinase kinase; p42/p44 mapk p42/p44 mitogen-activated protein kinase; Bcl-2 apoptosis regulator Bcl-2; p38 mitogen-activated protein kinase p38; JNK JUN N-terminal kinase; PLZF promyelocytic leukemia zinc finger protein; p85αPI3K phosphatidylinositol 3-kinase regulatory subunit alpha

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