Stimulation of AT2 receptor exerts beneficial effects in stroke-prone rats: Focus on renal damage

Department of Pharmacological Sciences, University of Milan, Milan, Italy.
Journal of Hypertension (Impact Factor: 4.72). 09/2009; 27(12):2444-51. DOI: 10.1097/HJH.0b013e3283311ba1
Source: PubMed


Angiotensin II acts through two major receptors: AT1-R and AT2-R. It is known that the stimulation of AT1-R mediates vasoconstriction, cell proliferation and fibrosis, aldosterone release and inflammatory response but, although the stimulation of AT2-R is thought to promote vasodilation and anti-inflammatory effects, its real in-vivo functions are still unclear. The aim of this study was to investigate the effects of specific and selective AT2-R stimulation on the pathological events occurring in spontaneously hypertensive stroke-prone rats (SHRSPs).
SHRSPs who were fed a high-salt diet underwent long-term treatment with vehicle or compound 21 (C21), a nonpeptide selective AT2-R agonist, at doses of 0.75, 5 and 10 mg/kg per day. The vehicle-treated rats developed brain abnormalities detectable by magnetic resonance imaging after 42.5 +/- 7.5 days, and died 43 +/- 9.5 days after the start of the dietary treatment. The highest C21 dose delayed the occurrence of brain damage (P < 0.001 vs. vehicle-treated SHRSPs) and prolonged survival (P < 0.001) without affecting blood pressure. These beneficial effects of C21 were abolished by the administration of PD123319, an AT2-R antagonist. C21 treatment preserved renal structure by preventing inflammatory cell infiltration, collagen accumulation, and the neo-expression of vimentin; it also prevented the increased plasma renin activity and accumulation of urinary acute-phase proteins observed in the vehicle-treated rats.
Specific and selective AT2-R stimulation has beneficial effects on the pathological events occurring in SHRSPs. These data indicate a new avenue for the pharmacological treatment of diseases in which modulation of the renin-angiotensin system is required.

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Available from: Marc de Gasparo, Nov 24, 2014
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    • "The AT2R agonist C21 is similar in size and structure to the nonpeptide AT1R antagonists (ARBs) in clinic and is highly selective for the AT2R, reported to be anywhere from <4,000-fold [17] to 25,000-fold [14] selective for AT2R over AT1R. In the setting of stroke, although not specifically assessing brain injury, Gelosa et al., found that oral administration of C21 delayed brain damage and extended life expectancy in stroke-prone hypertensive rats on a high sodium diet [18]. In light of our research illustrating the protective actions of the AT2R during cerebral ischemia, the aim of the current study was to examine whether the same degree of neuroprotection can be induced using the novel drug-like agonist C21, which is more clinically relevant than the previously studied peptide agonist CGP42112. "
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    ABSTRACT: In this study, the neuroprotective effect of a novel nonpeptide AT2R agonist, C21, was examined in a conscious model of stroke to verify a class effect of AT2R agonists as neuroprotective agents. Spontaneously hypertensive rats (SHR) were pre-treated for 5 days prior to stroke with C21 alone or in combination with the AT2R antagonist PD123319. In a separate series of experiments C21 was administered in a series of 4 doses commencing 6 hours after stroke. A focal reperfusion model of ischemia was induced in conscious SHR by administering endothelin-1 to the middle cerebral artery (MCA). Motor coordination was assessed at 1 and 3 days after stroke and post mortem analyses of infarct volumes, microglia activation and neuronal survival were performed at 72 hours post MCA occlusion. When given prior to stroke, C21 dose dependently decreased infarct volume, which is consistent with the behavioural findings illustrating an improvement in motor deficit. During the pre-treatment protocol C21 was shown to enhance microglia activation, which are likely to be evoking protection by releasing brain derived neurotrophic factor. When drug administration was delayed until 6 hours after stroke, C21 still reduced brain injury. These results indicate that centrally administered C21 confers neuroprotection against stroke damage. This benefit is likely to involve various mechanisms, including microglial activation of endogenous repair and enhanced cerebroperfusion. Thus, we have confirmed the neuroprotective effect of AT2R stimulation using a nonpeptide compound which highlights the clinical potential of the AT2R agonists for future development.
    Full-text · Article · Apr 2014 · PLoS ONE
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    • "SHR-SPs represent an animal model of hypertension, characterized by the progressive development of renal damage and brain abnormality against the background of elevated Ang II blood levels. Oral treatment with C21 (peak dosage group: 10 mg/kg, suspended release from 0.5% sodium carboxymethylcellulose) significantly delayed the development of proteinuria and prevented the accumulation of high-molecular-weight proteins, which present markers of renal inflammation, in 24-hour urine electrophoresis.58 Although plasma renin activity increased significantly in the vehicle group, plasma renin activity remained at basal levels in animals treated with C21. "
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    ABSTRACT: The angiotensin type 2 receptor (AT2R) and the receptor MAS are receptors within the renin-angiotensin system, which mediate tissue-protective actions such as anti-inflammation, antifibrosis, and antiapoptosis. In recent years, several programs have been launched in order to develop drugs that act as agonists on the AT2R or MAS to take therapeutic advantage of the protective and regenerative properties of these receptors. This review article will focus on recent data obtained in preclinical animal and in vitro models with new AT2R-agonistic molecules (Compound 21 and β-amino acid substituted angiotensin II) and with relevance for blood pressure (BP) regulation or hypertensive end-organ damage. These data will include studies on vasodilation/vasoconstriction in isolated resistance arteries ex vivo, studies on kidney function, studies on vascular remodeling, and studies that measured the net effect of AT2R stimulation on BP in vivo. Current data indicate that although AT2R stimulation causes vasodilation ex vivo and promotes natriuresis, it does not alter BP levels in vivo acutely - at least as long as there is no additional low-dose blockade of AT1R. However, AT2R stimulation alone is able to attenuate hypertension-induced vascular remodeling and reduce arterial stiffening, which in more chronic settings and together with the natriuretic effect may result in modest lowering of BP. We conclude from these preclinical data that AT2R agonists are not suitable for antihypertensive monotherapy, but that this new future drug class may be beneficial in combination with established antihypertensives for the treatment of hypertension with improved protection from end-organ damage.
    Full-text · Article · Nov 2013 · Integrated Blood Pressure Control
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    • "However, this hypothesis remains to be explored. Studies conducted to date with the selective AT 2 agonist C21/M024 do not describe such differences between C21/M024-treated animals compared to the control group [165] [166], suggesting that the duration of C21/M024 treatment may have been too short to induce any modification in body weight. Thus, in this latter instance, even if the AT 2 receptor was observed to decrease food intake, it was probably not sufficient to induce a decrease in body weight, at least following short periods of stimulation (<8 weeks). "
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    ABSTRACT: Angiotensin II (Ang II) is the main active product of the renin-angiotensin system (RAS), mediating its action via two major receptors, namely, the Ang II type 1 (AT(1)) receptor and the type 2 (AT(2)) receptor. Recent results also implicate several other members of the renin-angiotensin system in various aspects of brain functions. The first aim of this paper is to summarize the current state of knowledge regarding the properties and signaling of the AT(2) receptor, its expression in the brain, and its well-established effects. Secondly, we will highlight the potential role of the AT(2) receptor in cognitive function, neurological disorders and in the regulation of appetite and the possible link with development of metabolic disorders. The potential utility of novel nonpeptide selective AT(2) receptor ligands in clarifying potential roles of this receptor in physiology will also be discussed. If confirmed, these new pharmacological tools should help to improve impaired cognitive performance, not only through its action on brain microcirculation and inflammation, but also through more specific effects on neurons. However, the overall physiological relevance of the AT(2) receptor in the brain must also consider the Ang IV/AT(4) receptor.
    Full-text · Article · Dec 2012 · International Journal of Hypertension
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