AT2 Receptor and Tissue Injury: Therapeutic Implications

Pawel Namsolleck,Sébastien Foulquier,Ulrike Muscha Steckelings,Chiara Recarti,Thomas Unger

doi:10.1007/s11906-013-0416-6

Pawel Namsolleck, Sébastien Foulquier + Show 3 more

Open Access

https://doi.org/10.1007/s11906-013-0416-6

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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.

Highlights

Research on the AT2 receptor (AT2R) started about 25 years ago with the discovery of two receptors for angiotensin II (Ang II), the AT1 receptor (AT1R) and the AT2R
Opposed to the findings described above, a recent study showed that AT2R deficiency has no effect on either aortic aneurysms or atherosclerosis [73]
We have recently evaluated the impact of the direct AT2R stimulation with compound 21 (C21) on neuroregeneration in an animal model of spinal cord injury (SCI) [37]

Summary

Introduction

Research on the AT2 receptor (AT2R) started about 25 years ago with the discovery of two receptors for angiotensin II (Ang II), the AT1R and the AT2R. Key molecular mechanisms involved in the AT2R-mediated anti-inflammatory actions are the inhibition of NF-κB activity [17, 18] and the reduction of oxidative stress [19, 20] (Fig. 1). It has been speculated that the signaling cascades activated by NO, including cGMPdependent protein kinase activation, may be involved in downstream activation of mitogen-activated protein kinases that are required for IL-10 production [24] In agreement with this hypothesis, Dhande and colleagues have recently demonstrated anti-inflammatory actions of the AT2R via increased interleukin (IL-10) production in an NO-dependent manner [25]. An important mechanism of AT2R-mediated anti-fibrosis appears to be an increased expression and activity of TIMP1 and TIMP2 with consequent inhibition of MMP9 and MMP2; the exact signaling pathway is still unknown. A higher level of complexity has been added to the growth effects of the AT2R after the discovery of the promyelocytic leukemia zinc finger protein (PLZF) as an interacting protein of the AT2R [47], see below (Fig. 1)

Neuronal Regeneration

Vascular Protection

Conclusions

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