AT2 Receptor and Tissue Injury: Therapeutic Implications

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.

Preservation of Glucagon-Like Peptide-1 Level Attenuates Angiotensin II-Induced Tissue Fibrosis by Altering AT1/AT2 Receptor Expression and Angiotensin-Converting Enzyme 2 Activity in Rat Heart

“…Immunohistochemical staining revealed that these two receptors are mainly localized in the myocardium and perivascular vessels. The dual effects of liraglutide and linagliptin on AT 1 and AT 2 receptors further indicated that there is a cross talk between these two receptors, consistent with previous reports showing that down-regulation of the AT 1 receptor by the AT 1 receptor blocker up-regulates the AT 2 receptor [5,23]. Macrophages indisputably play a key role in all stages of the fibrotic process, and can be activated by Ang II through stimulating the AT 1 receptors on infiltrating macrophages.…”

“…Stimulation of the AT 1 receptor increases blood pressure by constricting blood vessels, whereas activation of the AT 2 receptor has a diametrically opposed effect, i.e., lowering blood pressure by vasodilation [5]. Accordingly, lowering blood pressure by a AT 1 receptor blocker has been shown to inhibit fibrotic formation [31].…”

“…Through stimulating the Ang II type I (AT 1 ) receptor, Ang II induces vascular constriction, systemic inflammatory response, interstitial collagen deposition and tissue fibrosis. However, Ang II is also believed to have beneficial cardiovascular effects by its potential countervailing effects to the AT 1 receptor [4,5]. Therefore, the current strategy for cardioprotection is to decrease Ang II formation or AT 1 receptor activation with Ang II-converting enzyme inhibitors (ACEi) [6] or AT 1 receptor blocker (ARBs) [7].…”

Renin inhibitor aliskiren exerts beneficial effect on trabecular bone by regulating skeletal renin-angiotensin system and kallikrein-kinin system in ovariectomized mice

“…Several publications raised the possibility that AT1R and AT2R carry out negative cross-talk within fibroblasts and vascular endothelial cells with respect to each other's signaling pathways and responses [49]. This study revealed that the expression of AT2R was lower in OVX mice than that in Sham mice, which was consistent with that AT2R is the protective arm of RAS and counterbalances pathological processes and enable recovery from disease [50,51]. Of importance, the oppose regulation of aliskiren on AT1R and AT2R showed the unique characteristic of renin inhibitor, which contributed to its protective effects against bone deteriorations by interacting with Ang II signaling pathways.…”

Involvement of the Renin‐Angiotensin System in Atherosclerosis

“…However, whether the stimulation of the AT2R is protective or deleterious in human atherosclerosis remains unresolved. The impact of AT2R during atherosclerosis or tissue injury should be studied by direct stimulation of AT2R to address potential therapeutic potential [164,165].…”