Non-peptide AT2-receptor agonists

Steckelings, Ulrike Muscha; Larhed, Mats; Hallberg, Anders; Widdop, Robert E; Jones, Emma S; Wallinder, Charlotta; Namsolleck, Pawel; Dahlöf, Björn; Unger, Thomas

doi:10.1016/j.coph.2010.11.002

Cited by 93 publications

(80 citation statements)

References 35 publications

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“…There are now agonists to both the AT 7 and AT 2 receptors that may potentially be combined with a renin inhibitor to preserve these receptor pathways while blocking the ANG II-AT 1 axis of the RAS. Moreover, both the AT 7 agonist AVE0992 and the AT 2 agonist C21 are nonpeptides that should access the cell membrane and activate intracellular or nuclear receptors (49,73,93,103). Aliskiren and ARBs are also nonpeptides that may target intracellular as well as extracellular sites, although ARBs exhibit different degrees of lipophilicity, which may influence the extent of their tissue permeability (52).…”

Section: Perspectives and Significancementioning

confidence: 99%

Review:Novel roles of nuclear angiotensin receptors and signaling mechanisms

Gwathmey

Alzayadneh

Pendergrass

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

110

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The renin-angiotensin system (RAS) constitutes an important hormonal system in the physiological regulation of blood pressure. The dysregulation of the RAS is considered a major influence in the development and progression of cardiovascular disease and other pathologies. Indeed, experimental and clinical evidence indicates that blockade of this system with angiotensin-converting enzyme (ACE) inhibitors or angiotensin type 1 receptor (AT 1R) antagonists is an effective therapy to attenuate hypertension and diabetic renal injury, and to improve heart failure. Originally defined as a circulating system, multiple tissues express a complete RAS, and compelling evidence now favors an intracellular system involved in cell signaling and function. Within the kidney, intracellular expression of the three predominant ANG receptor subtypes is evident in the nuclear compartment. The ANG type 1 receptor (AT 1R) is coupled to the generation of reactive oxygen species (ROS) through the activation of phosphoinositol-3 kinase (PI3K) and PKC. In contrast, both ANG type 2 (AT 2R) and ANG-(1-7) (AT 7R) receptors stimulate nitric oxide (NO) formation, which may involve nuclear endothelial NO synthase (eNOS). Moreover, blockade of either ACE2-the enzyme that converts ANG II to ANG-(1-7)-or the AT 7 receptor exacerbates the ANG II-ROS response on renal nuclei. Finally, in a model of fetal programmed hypertension, the nuclear ROS response to ANG II is enhanced, while both AT 2 and AT7 stimulation of NO is attenuated, suggesting that an imbalance in the intracellular RAS may contribute to the development of programming events. We conclude that a functional intracellular or nuclear RAS may have important implications in the therapeutic approaches to cardiovascular disease. renin-angiotensin system; angiotensin converting enzyme; ACE2; neprilysin; kidney; nuclei; AT 1 ; AT 2 ; AT 7 , FROM THE EARLY STUDIES OF Tigerstedt and Bergman (101) that described renin activity in the kidney to the characterization of a pressor substance subsequently identified as ANG II by the laboratories of Braun-Menendez (6) (hypertensin) and Page (angiotonin) 50 years later (8), the characterization of the renin-angiotensin system (RAS) within the kidney and other tissues continues unabated to broaden our understanding of the functional aspects of this important hormonal system in blood pressure regulation and cardiovascular pathologies. Coupled with the discoveries of ANG I-converting enzyme (ACE) as the primary enzyme that forms ANG II in the circulation and tissue and the molecular identification of the ANG II type 1 receptor (AT 1 ) that confers the predominant actions of ANG II, the "classical" RAS was regarded as a sequential endocrine system to form ANG II for the maintenance of blood pressure through renal, vascular, and central mechanisms. There is, however, overwhelming evidence for a "nonclassical" RAS that results in the formation of novel peptide products with functional properties distinct from that of the ANG II-AT 1 receptor pathway (5,12,14,67,8...

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Section: Perspectives and Significancementioning

confidence: 99%

Review:Novel roles of nuclear angiotensin receptors and signaling mechanisms

Gwathmey

Alzayadneh

Pendergrass

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

110

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“…multiple sclerosis, rheumatoid arthritis) diseases. 4,[19][20][21] Due to this broad spectrum of potential indications, the decision about a first clinical indication will be based on further parameters such as duration/size/costs of phase II and III studies and the putative future market situation.…”

Section: At2-receptor Agonistsmentioning

confidence: 99%

New therapeutic pathways in the RAS

Bäder

Santos

Unger

et al. 2012

J Renin Angiotensin Aldosterone Syst

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“…The well-known hemodynamic (i.e., vasoconstriction) or cellular effects (i.e., profibrotic and proinflammatory effects) of angiotensin II are mediated by AT 1 receptors, while the stimulation of AT 2 receptors counteracts AT 1 receptor-mediated effects either directly or by modulating AT 1 receptor signaling (15,16,18,25). Furthermore, AT 1 receptor blockade, as occurs with angiotensin receptor blocker treatment, could promote the stimulation of AT 2 receptors by elevated levels of circulating angiotensin II.Compound 21 (C21), a nonpeptide, highly selective AT 2 receptor agonist (34), directly stimulates AT 2 receptors, thus opening the way to the comprehension of AT 2 receptor-mediated effects (30,31). Increasing data demonstrate that C21 administration improves cardiac function in rat with myocardial infarction (15, 16), reduces myocardial and vascular fibrosis in stroke-prone spontaneously hypertensive rats (24), and prevents aortic stiffening and collagen deposition in an experimental model of N -nitro-L-arginine-methyl ester-induced hypertension (20).…”

mentioning

confidence: 99%

“…Compound 21 (C21), a nonpeptide, highly selective AT 2 receptor agonist (34), directly stimulates AT 2 receptors, thus opening the way to the comprehension of AT 2 receptor-mediated effects (30,31). Increasing data demonstrate that C21 administration improves cardiac function in rat with myocardial infarction (15, 16), reduces myocardial and vascular fibrosis in stroke-prone spontaneously hypertensive rats (24), and prevents aortic stiffening and collagen deposition in an experimental model of N -nitro-L-arginine-methyl ester-induced hypertension (20).…”

mentioning

confidence: 99%

Prevention of diabetic nephropathy by compound 21, selective agonist of angiotensin type 2 receptors, in Zucker diabetic fatty rats

Castoldi

Gioia

Bombardi

et al. 2014

American Journal of Physiology-Renal Physiology

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The aim of this study was to evaluate the effect of compound 21 (C21), a selective AT 2 receptor agonist, on diabetic nephropathy and the potential additive effect of C21, when associated with losartan treatment, on the development of albuminuria and renal fibrosis in Zucker diabetic fatty (ZDF) rats. The experiments lasted 15 wk (from 5 to 20 wk of age) and were performed in 40 ZDF rats and 12 control lean rats. ZDF rats were divided into 4 groups: 1) 9 rats were treated with losartan; 2) 10 rats were treated with C21; 3) 9 rats were treated with losartan plus C21; and 4) 12 rats were maintained without any treatment. ZDF rats showed an increase in blood glucose level, albuminuria, renal fibrosis, macrophage infiltration, and TNF-␣ expression and a reduction of glomerular nephrin expression compared with control lean rats. C21 treatment reduced renal glomerular, tubulointerstitial, and perivascular fibrosis, and macrophage infiltration and TNF-␣ expression in ZDF rats. C21 treatment caused a decrease in albuminuria in ZDF rats up to 11 wk of age. Losartan decreased macrophage infiltration, TNF-␣ expression, and renal glomerular and perivascular fibrosis, restored glomerular nephrin expression, but did not affect tubulointerstitial fibrosis. Losartan treatment caused a decrease in albuminuria in ZDF rats up to 15 wk of age. At the end of the protocol, only the combination of C21 plus losartan significantly reduced albuminuria in ZDF rats. These data demonstrate that C21 has beneficial effects on diabetic nephropathy, suggesting the combination of C21 and losartan as a novel pharmacological tool to slow the progression of nephropathy in type II diabetes. diabetic nephropathy; compound 21; urinary albumin excretion; experimental models; renal fibrosis; Zucker diabetic fatty rats DIABETIC NEPHROPATHY IS STILL the worldwide leading cause of end-stage renal disease (2,26,35). In the case of diabetes, hyperglycemia is undoubtedly the determining cause for the development of nephropathy, but often in diabetic patients concomitant factors, such as high blood pressure, dyslipidemia, and the presence of albuminuria, accelerate the progression of renal disease. Consequently, in addition to a tight correction of blood glucose levels, a careful control of blood pressure, dyslipidemia, and albuminuria are essential to slow down the progression of nephropathy (3,32,33).Angiotensin II, the main effector of the renin-angiotensin system, plays a key role in the progression of diabetic nephropathy. Accordingly, drugs acting on the renin-angiotensin system, by inhibiting angiotensin-converting enzyme or by blocking angiotensin II type 1 (AT 1 ) receptors, are the treatment of choice for diabetic nephropathy. Angiotensin II binds to two G protein-coupled receptors, the AT 1 and the angiotensin II type 2 (AT 2 ) receptors. The well-known hemodynamic (i.e., vasoconstriction) or cellular effects (i.e., profibrotic and proinflammatory effects) of angiotensin II are mediated by AT 1 receptors, while the stimulation of AT 2 receptors coun...

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Non-peptide AT2-receptor agonists

Cited by 93 publications

References 35 publications

Review:Novel roles of nuclear angiotensin receptors and signaling mechanisms

Review:Novel roles of nuclear angiotensin receptors and signaling mechanisms

New therapeutic pathways in the RAS

Prevention of diabetic nephropathy by compound 21, selective agonist of angiotensin type 2 receptors, in Zucker diabetic fatty rats

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