The Novel AT2 Receptor Agonist β-Pro7-AngIII Exerts Cardiac and Renal Anti-Fibrotic and Anti-Inflammatory Effects in High Salt-Fed Mice

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 (AT(2)R) has been considered as organ protective in many CVDs. However, there are limited AT(2)R-selective agonists available. Our first reported beta-substituted angiotensin III peptide, beta-Pro(7)-AngIII, showed high selectivity for the AT(2)R. In the current study, we examine the potential anti-fibrotic and anti-inflammatory effects of this novel AT(2)R-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-beta 1 levels in heart, kidney and plasma. Four weeks' treatment (from weeks 5-8) with beta-Pro(7)-AngIII inhibited the HS-induced cardiac and renal fibrosis and inflammation. These protective effects were accompanied by reduced local and systemic TGF-beta 1 as well as reduced cardiac myofibroblast differentiation. Importantly, the anti-fibrotic and anti-inflammatory effects caused by beta-Pro(7)-AngIII were attenuated by the AT(2)R antagonist PD123319. These results demonstrate, for the first time, the cardio- and reno-protective roles of the AT(2)R-selective beta-Pro(7)-AngIII, highlighting it as an important therapeutic that can target the AT(2)R to treat end-organ damage.