A high salt (HS) diet is associated with an increased risk for cardiovascular diseases (CVDs) and fibrosis is a key contributor to the organ dysfunction involved in CVDs. The activation of the renin angiotensin type 2 receptor (AT₂R) has been considered as organ protective in many CVDs. However, there are limited AT₂R-selective agonists available. Our first reported β-substituted angiotensin III peptide, β-Pro⁷-AngIII, showed high selectivity for the AT₂R. In the current study, we examine the potential anti-fibrotic and anti-inflammatory effects of this novel AT₂R-selective peptide on HS-induced organ damage. FVB/N mice fed with a 5% HS diet for 8 weeks developed cardiac and renal fibrosis and inflammation, which were associated with increased TGF-β1 levels in heart, kidney and plasma. Four weeks’ treatment (from weeks 5–8) with β-Pro⁷-AngIII inhibited the HS-induced cardiac and renal fibrosis and inflammation. These protective effects were accompanied by reduced local and systemic TGF-β1 as well as reduced cardiac myofibroblast differentiation. Importantly, the anti-fibrotic and anti-inflammatory effects caused by β-Pro⁷-AngIII were attenuated by the AT₂R antagonist PD123319. These results demonstrate, for the first time, the cardio- and reno-protective roles of the AT₂R-selective β-Pro⁷-AngIII, highlighting it as an important therapeutic that can target the AT₂R to treat end-organ damage.

Class A, rhodopsin‐like, G‐protein‐coupled receptors (GPCRs) are by far the largest class of GPCRs and are integral membrane proteins used by various cells to convert extracellular signals into intracellular responses. Initially, class A GPCRs were believed to function as monomers, but a growing body of evidence has emerged to suggest that these receptors can function as homodimers and heterodimers and can undergo functional crosstalk to influence the actions of agonists or antagonists acting at each receptor. This review will focus on the angiotensin type 1 (AT₁) and type 2 (AT₂) receptors, as well as the relaxin family peptide receptor 1 (RXFP1), each of which have their unique characteristics but have been demonstrated to undergo some level of interaction when appropriately co‐expressed, which influences the function of each receptor. In particular, this receptor functional crosstalk will be discussed in the context of fibrosis, the tissue scarring that results from a failed wound‐healing response to injury, and which is a hallmark of chronic disease and related organ dysfunction.LINKED ARTICLES: This article is part of a themed issue Therapeutic Targeting of G Protein‐Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc

Angiotensin II AT2 receptor (AT2R) activation leads to significant anti-fibrotic and anti-inflammatory effects in diseased organs, which has led to clinical trial evaluation of the AT2R agonist, Compound 21 (C21), as a treatment for idiopathic pulmonary fibrosis (IPF). In this study, the anti-fibrotic effects of a more selective AT2R ligand, β-Pro7 angiotensin III (β-Pro7 Ang III), with >20,000-fold affinity for the AT2R over the AT1R, were compared with that of C21 or the currently used IPF medication, pirfenidone, in mice with bleomycin (BLM)-induced pulmonary fibrosis. Adult female BALB/c mice received a double intranasal instillation of BLM (20 mg/kg/day) seven days apart and were maintained until day 35, while control mice were instilled with saline (SAL) seven days apart and maintained for the same time period. Sub-groups of BLM-injured mice were then treated on day 28 with vehicle (SAL), C21 (0.3 mg/kg/day) or β-Pro7 Ang III (0.1 mg/kg/day) via seven-day subcutaneously implanted osmotic minipumps, or daily from days 28 to 35 via orally administered pirfenidone (100 mg/kg/day). At day-35 post-injury, measures of lung fibrosis and compliance were evaluated. Compared with their SAL-instilled counterparts, SAL-treated BLM-injured mice presented with a significantly increased lung Ashcroft score, Masson’s trichrome-stained and second harmonics generation-measured fibrosis, myofibroblast accumulation, and TGF-β1 expression, but reduced lung dynamic compliance at day-35 post-injury. While all treatments evaluated attenuated the BLM-induced lung myofibroblast accumulation and TGF-β1 expression, AT2R stimulation, but not pirfenidone, attenuated lung collagen deposition after seven days. β-Pro7 Ang III also significantly restored lung compliance and promoted collagen-degrading matrix metalloproteinase-2 activity. These findings highlighted the therapeutic value of selectively targeting the AT2R for treating IPF.