TABLE 1.
Actions of angiotensin II
| Effect | Target | Mechanism: Intracellular Pathways Elicited |
|---|---|---|
| Actions in the kidney | ||
| Sodium and water retention | Renal microvasculature | Reduces GFR and renal plasma flow through the following: Afferent and efferent vasoconstriction via AT1 receptor activation (Navar et al., 1996; Arendshorst et al., 1999). Filtration coefficient reduction, probably due to constriction of mesangial cells (Blantz et al., 1976; Baylis and Brenner, 1978). Increased sensitivity of tubule-glomerular feedback mechanism via AT1 receptor activation in mesangial cells (Schnermann and Briggs, 1986; Mitchell and Navar, 1988) and increased activity of Na/H exchanger (Peti-Peterdi and Bell, 1998) and Na+/K+/2Cl- transporter (Kovács et al., 2002). |
| Proximal tubule | Increases sodium reabsorption at physiologic concentrations (Harris and Young, 1977; Schuster et al., 1984) via activation of Na+/H+ exchanger, basolateral Na+/K+ ATPase and H+-ATPase (Wang and Giebisch, 1996). AT1 receptor activation in proximal tubule cells leads to activation of multiple signaling pathways (including phospholipase C, D, and A2; Src-MAPK, and tyrosine kinases), increase in intracellular calcium, and inhibition of adynlyl cyclase (Zhuo and Li, 2007). | |
| Thick ascending limb | Stimulates Na+-K+-2Cl-transporter activity (Kovács et al., 2002). AT1 receptor activation leads to increases in Gq–PKCα and NADPH oxidase and superoxide production(Herrera et al., 2010). | |
| Distal tubule | Stimulates Na+/H+ exchanger activity (Barreto-Chaves and Mello-Aires, 1996). | |
| Collecting duct | Activates ENaC through stimulation of aldosterone secretion by adrenal glands (Navar et al., 1996), and directly via AT1 receptor (Peti-Peterdi et al., 2002). Increases urea transport (Kato et al., 2000). | |
| Cell hypertrophy, fibrosis, and matrix remodeling | Whole kidney | Most actions are due to induction of TGF-β. Other factors include endothelin-1, MMP-2, and hypoxia (Rüster and Wolf, 2011). |
| Oxidative stress | Whole kidney | Induces assembly and activation of the NADPH oxidase complex (Sachse and Wolf, 2007). ROS activates several pathways, including MAP kinases, NF-κB, tyrosine kinases, metalloproteinases, and AP-1 (Sachse and Wolf, 2007). |
| Inflammation | Whole kidney | AT1 receptor–mediated upregulation of proinflammatory genes, such as VCAM-1, ICAM-1, IL-6, TNFα, and MCP-1. Activation of multiple pathways, including NF-κB, MAPK cascade, Rho proteins, and ROS (Ruiz-Ortega et al., 2006a, b). |
| Actions in the vasculaturea | ||
| Vasoconstriction | VSMC | AT1 receptor–mediated activation of G proteins, including Gq/11, G12, and G13, leads to increases in several second messengers, including intracellular calcium, IP3, ROS, and Rho kinase and ARHGEF1 factor (Guilluy et al., 2010). |
| Growth, inflammation/ fibrosis | VSMC | AT1 receptor–mediated activation of MAPKs (including P38 and ERK), JNK, and tyrosine kinases (SRC, JAK, FAK, PYK2, P130Cas), intracellular calcium increases and ROS (Touyz et al., 1999; Savoia et al., 2011). Transactivation of receptor tyrosine kinases such as EGF, PDGF, and IGF1 (Saito and Berk, 2001). Increased production of endothelin-1, TGF-β, bFGF, and IGF1. |
| Vasodilation | VSMC | AT2 receptor–mediated activation of NO-GMP pathway (Savoia et al., 2011) or through bradykinin (Savoia et al., 2011). AT2 receptor activation is also associated with other antiproliferative and anti-inflammatory effects. |
| Actions in the heart | ||
| Increased inotropism | Ventricular myocardium | Increases inotropism indirectly by stimulating the sympathetic nervous system (Koch-Weser, 1965) and directly by intracellular calcium influx and changes of the plateau phase of the cardiac action potential (Dempsey et al., 1971). |
| Papillary muscles | Induces release of endothelin, which activates the Na+/H+ exchanger, increases [Na+]i, and promotes the influx of Ca2+ that leads to a positive inotropic effect (Perez et al., 2003). Stretch of papillary muscles induces the release of angiotensin II (Cingolani et al., 2005). | |
| Hypertrophy | Whole heart | Several reports indicate that local AT1 receptor stimulation induces cardiac hypertrophy (Dostal and Baker, 1998). However, others have shown that local increase of angiotensin II production in the heart does not produce cardiac hypertrophy (Xiao et al., 2008), and that AT1 receptor exclusively in the kidneys is sufficient to induce hypertension and cardiac hypertrophy (Crowley et al., 2006). |
| Left ventricle | Leads to diastolic dysfunction as a consequence of impaired diastolic sarcoplasmic reticulum calcium pump (SERCA2) activity via AT1 receptor (Rothermund et al., 2001). Promotes myocardial distensibility through AT1 receptor. May be an important adaptive mechanism in an acute overload context (Castro-Chaves et al., 2009). | |
| Cultured cardiomyocytes | Mediates myocyte hypertrophy through AT1 receptor (van Kesteren et al., 1997) and release of endothelin-1 and TGF-β by cardiac fibroblasts (Gray et al., 1998). Stimulates cardiac growth via AT1 receptor–induced JAK-STAT signaling activation (McWhinney et al., 1997). Mediates stretch-induced hypertrophy via AT1 receptor (Sadoshima et al., 1993). Induces hypertrophy through AT1 receptor independently of blood pressure elevation (Ainscough et al., 2009). Aldosterone receptor activation boosts angiotensin II–induced expansion of extracellular matrix proteins, fibrosis, and oxidative stress (Di Zhang et al., 2008). | |
| Remodeling and dysfunction | Whole heart | Produces multifocal antimyosin labeling of cardiac myocytes and myocytolysis (Tan et al., 1991). Contributes to arrhythmogenic atrial structural remodeling by MAPK activation (Li et al., 2001). Leads to cardiac dysfunction in absence of hemodynamic overload (Domenighetti et al., 2005). |
| Fibroblasts | Induces fibrosis at least partially mediated through TGF-β production via AT1 receptor activation (Pinto et al., 2000). Generates proliferative stimuli for the fibroblast portion of cardiac cell population (Schelling et al., 1991). Increases DNA synthesis rate and proliferation of fibroblast (Tan et al., 1991). | |
| Cultured cardiomyocytes | Increases mRNA and protein levels of osteopontin through AT1 receptor (Ashizawa et al., 1996). | |
| Induces periostin expression through the activation of the Ras/p38 MAPK/CREB and the ERK1/2/TGF-β pathways (Li et al., 2011). | ||
| Induces apoptosis through AT receptor (Cigola et al., 1997). | ||
| Leads to a proinflammatory/profibrogenic phenotype and enhances reactive oxygen species production (Zhao et al., 2006). | ||
| Apoptosis and Inflammation | Aortic endothelial cells | Induces mitochondrial dysfunction via a protein kinase C-dependent pathway by activating the endothelial cell NADPH oxidase and formation of peroxynitrite (Doughan et al., 2008). |
| Actions in the central nervous system | ||
| Blood pressure regulation | NTS | Baroreceptor reflex suppression through: AT receptor activation (Lucius et al., 1998; Paul et al., 2006) and inhibition of ACE2 activity (Xia et al., 2009). Increases expression of GABAb receptor that could contribute to baroreceptor reflex suppression (Yao et al., 2008). |
| RVLM, PVN, SFO | Increased sensitivity of cardiac sympathetic afferents via AT1 receptor (Epstein et al., 1970; Xia et al., 2009). | |
| Supraoptic nuclei, PVN | Increases vasopressin released via AT1 receptor (Qadri et al., 1993). | |
| MnPO, OVLT, SFO, CVOs, and limbic structures | Increases water intake and NaCl intake via AT1 receptor activation (Mathai et al., 1997; Weisinger et al., 1997). The dipsogenic action involves participation of catecholamines released from neurons (Grossman, 1962) and could be mediated by NMDA receptors (Xu et al., 1997). | |
| Induces chronic activation of renal sympathetic nerve shifting renal function to higher blood pressure levels (Osborn and Camara, 1997). | ||
| The combination of angiotensin II and high salt intake increases splanchnic SNA and decreased renal SNA, creating a hemodynamic environmnet capable of producing sustained hypertension (Osborn and Fink, 2010). | ||
| Augments fluid intake and generates polyuria and chronic hyponatremia via AT1 receptor and increased adrenal steroids (Grobe et al., 2010). | ||
| Metabolism | Hypothalamus: increases metabolism and anorexigenic effect | Regulates food intake and weight gain through release of anorexigenic neuropeptide Crh via AT1 receptor (Yamamoto et al., 2011). |
| ICV infusion: promotes negative energy balance | Augments whole-body heat production and oxygen consumption, and reduces body adipose mass through increased sympathetic activation via increased β3-adrenergic receptor expression in brown and white adipose tissue (de Kloet et al., 2011). Induces a profound reduction in both subcutaneous and visceral adiposity (Grobe et al., 2010). Leads to enhanced brown adipose tissue thermogenesis and white adipose tissue lipolysis, possibly through AT2 receptor (Watanabe et al., 1999; de Kloet et al., 2011). | |
| Nervous system development | Microexplant cultures of the cerebellum | Increases elongation of neurites and cell migration in rat neonates via AT2 receptor (Cote et al., 1999). |
| Optic nerve | Promotes differentiation and axonal regeneration, and inhibits proliferation of neuronal cells via AT2 receptor stimulation (Lucius et al., 1998). | |
| Cultured neurons | Enhances UV radiation–induced apoptosis through AT2 receptor (Shenoy et al., 1999). After focal brain injury, can prevent damage of neurons or activate neural repair systems through AT2 receptor (Mogi et al., 2006). | |
| Reproductive system | Pituitary cells | Increases prolactin release and regulates intracellular Ca2+ levels (Diaz-Torga et al., 1998). |
| Visual system | Superior colliculus | Reduces the amplitude of visual evoked potentials through AT1 receptor (Merabet et al., 1997; Coude et al., 2000). |
| Behavior | Left CA1 hippocampal area | Facilitates learning and memory of rats (Belcheva et al., 2000). Increases the pain threshold through AT2 receptor (Georgieva and Georgiev, 1999). |
| Sympathetic nervous system | Superior cervical ganglia cells, sympathetic region of the thoracic and lumbar spinal cord | Increases the excitability and facilitates the action potential-induced release of norepinephrine (Lewis and Coote, 1993; Osborn et al., 2011). |
| Parasympathetic nervous system | Preganglionic neurons | Inhibits release of acetylcholine via a presynaptic mechanism (Potter, 1982). |
| Actions in the digestive system | ||
| Digestion and water and electrolyte absorption | Small intestine | Increases bicarbonate secretion (Johansson et al., 2001) and sodium and water retention, directly or through stimulation of sympathetic nervous system (Levens et al., 1981; Garg et al., 2012). |
| Large intestine | Increases sodium and water reabsorption (de los Rios et al., 1980), modulation of colonic motility (Fishlock and Gunn, 1970). | |
| Esophagus | Increases motility (Casselbrant et al., 2007). | |
| Inflammation | Stomach | High expression of AT1 receptor in Helicobacter pylori (Hallersund et al., 2011). Greater expression of AT1 receptor in cancer cells than in normal tissue (Kinoshita et al., 2009). Angiotensin II stimulates MAPK kinase, NF-κB, and surviving activation in cancer cells in vitro (Kinoshita et al., 2009). |
| Small and large intestine | Mucosal levels of angiotensin II are elevated in patients with Crohn’s colitis (Jaszewski et al., 1990). ARBs and ACE inhibitors have beneficial effects in rodent models of intestinal inflammation and autoimmune diseases. Reviewed in Garg et al. (2012). | |
| Actions in the clotting system | ||
| Platelet aggregation | Platelet | Increases platelet aggregation by a mechanism that involves AT1 receptor, AT2 receptor, and AT4 receptor (Senchenkova et al., 2010). Stimulates platelet activating factor synthesis (Neuwirth et al., 1989). Induces platelet activation through thromboxane A2 with a resultant increase in the initiation of coagulation (Farmer, 2000). Increases plasma β-thromboglobulin levels, surface expression of P-selectin, and platelet fibrinogen binding (Larsson et al., 2000). Induces changes in the cytosolic platelet proteome suggestive of premature aging of platelets (Gebhard et al., 2011). Elicits a dose- and time-dependent increase in platelet-leukocyte-endothelial cell interactions (Ishikawa et al., 2007). |
| Cerebral endothelial cells | Causes mild activation of the coagulation cascade with increases in plasma levels of thrombin-antithrombin complex and prothrombin fragment F1 + 2 (Larsson et al., 2000). | |
| Coagulation | Coagulation cascade proteins | Accelerates thrombosis (Senchenkova et al., 2010). |
| Thrombosis and fibrinolysis | Arterioles | At physiologic levels, stimulates PAI-1 production by bovine aortic endothelial cells (Vaughan et al., 1995). |
| Endothelial cells | Possibly AT4 receptor (Vaughan, 1997). Augments tissue factor expression, thus promoting thrombosis (Nishimura et al., 1997). | |
| T lymphocytes | T lymphocytes (CD4+ and CD8+) and NADPH oxidase-derived reactive oxygen species play a major role in mediating the accelerated microvascular thrombosis associated with angiotensin II–induced hypertension (Senchenkova et al., 2011). Angiotensin II–induced PAI-1 synthesis is mediated by AT1 receptor (Goodfield et al., 1999). | |
| Actions in the liver | ||
| Hemodynamics | Hepatocytes | Stimulates angiotensinogen synthesis by inhibiting adenylyl cyclase activity and stabilizing angiotensinogen mRNA (Klett et al., 1993). |
| In vivo | Decreases hepatic blood flow (Messerli et al., 1977) and raises portal pressure (Vlachogiannakos et al., 2001). | |
| Metabolism | Hepatocytes | Degrades glycogen (Hems et al., 1978) and stimulates gluconeogenesis (Whitton et al., 1978) through a non-Ca2+-dependent mechanism. |
| In vivo | Induces hyperglycemic effects by increased hepatic glucose output (Rao, 1996). Reduces triglyceride content in the liver via an AT1 receptor–dependent mechanism (Ishizaka et al., 2011). | |
| Inflammation | In vivo | Generates infiltration of inflammatory cells, oxidative stress, increases intercellular adhesion molecule and interleukin-6 hepatic gene expression (Moreno et al., 2009), activates NF-κB through ubiquitination of IKKβ via AT1 receptor (McAllister-Lucas et al., 2007). Generates hepatic steatosis via AT1 receptor (Nabeshima et al., 2009). |
AP-1, activator protein-1; ARB, angiotensin receptor blocker; ARHGEF1, Rho guanine nucleotide exchange factor 1; AT1, angiotensin II type 1 receptor; bFGF, basic fibroblast growth factor; CA1, carbonic anhydrase 1; CREB, cAMP response element-binding protein; Crh, corticotropin-releasing hormone; CVO, circumventricular organ; EGF, epidermal growth factor; ENaC, epithelial sodium channel; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; GFR, glomerular filtration rate; ICAM-1, intercellular adhesion molecule-1; ICV, intracerebroventricular; IGF1, insulin-like growth factor 1; IKKβ, IκB kinase complex; IP3, inositol trisphosphate; JAK, Janus tyrosine kinase; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein-1; MMP-2, matrix metalloproteinase-2; MnPO, median preoptic nucleus; NF-κB, nuclear factor-κB; NMDA, N-methyl-d-aspartate; NO-GMP, nitric oxide-guanosine monophosphate; NTS, nucleus tractus solitarii; OVLT, organum vasculosum of the lamina terminalis; PAI-1, plasminogen activator inhibitor type 1; P130Cas, p130 Crk-associated substrate; PKCα, protein kinase Cα; PDGF, platelet-derived growth factor; PVN, paraventricular nucleus; PYK2, proline-rich tyrosine kinase 2; ROS, reactive oxygen species; RVLM, rostral ventrolateral medulla; SERCA2, sarco(endo)plasmic reticulum Ca2+ ATPase 2; SFO, subfornical organ; SNA, sulfosuccinimidyl acetate; SRC, Src (Sarcoma) family of tyrosine kinase; STAT, signal transducer and activator of transcription; VCAM-1, vascular cell adhesion molecule-1; VSMC, vascular smooth muscle cell.
a
Only angiotensin II effects on microvasculature are discussed.