Relaxin requires the angiotensin II type 2 receptor to abrogate renal interstitial fibrosis

Abstract

Fibrosis is a hallmark of chronic kidney disease, for which there is currently no effective cure. The hormone relaxin is emerging as an effective antifibrotic therapy; however, its mechanism of action is poorly understood. Recent studies have shown that relaxin disrupts the profibrotic actions of transforming growth factor-β1 (TGF-β1) by its cognate receptor, relaxin family peptide receptor 1 (RXFP1), extracellular signal-regulated kinase phosphorylation, and a neuronal nitric oxide synthase-dependent pathway to abrogate Smad2 phosphorylation. Since angiotensin II also inhibits TGF-β1 activity through its AT2 receptor (AT2R), we investigated the extent to which relaxin interacts with the AT2R. The effects of the AT2R antagonist, PD123319, on relaxin activity were examined in primary rat kidney myofibroblasts, and in kidney tissue from relaxin-treated male wild-type and AT2R-knockout mice subjected to unilateral ureteric obstruction. Relaxin's antifibrotic actions were significantly blocked by PD123319 in vitro and in vivo, or when relaxin was administered to AT2R-knockout mice. While heterodimer complexes were formed between RXFP1 and AT2Rs independent of ligand binding, relaxin did not directly bind to AT2Rs but signaled through RXFP1-AT2R heterodimers to induce its antifibrotic actions. These findings highlight a hitherto unrecognized interaction that may be targeted to control fibrosis progression.

The angiotensin II type 2 receptor agonist Compound 21 is protective in experimental diabetes-associated atherosclerosis

“…This is consistent with the view that the agonist most likely mediates its actions by influencing post-receptor signalling pathways. Indeed, recent studies have demonstrated that AT 2 R inhibits AT 1 Rmediated effects by targeting its downstream effectors, including TGF-β1 [41] and NOX [29], as well as its ability to activate vasoconstriction inhibiting factor, an endogenous co-factor of Ang II [42]. Moreover, with previous studies demonstrating that AT 2 R forms a heterodimer receptor complex with AT 1 R to block the signalling and mediated functions of the latter [43], it is possible that some of the Based on our findings that C21 exhibits similar antiatherogenic efficacy as candesartan and that the effects of candesartan could be inhibited in the presence of the AT 2 R antagonist PD123319, this could indicate that candesartanmediated actions occur at least in part as a result of the unopposed action of the AT 2 R. Consistent with these findings are studies, albeit in the non-diabetic setting, where candesartanmediated reduction of infarct size in pigs [44] and inhibition of cardiac remodelling in rats [45] were found to be dependent on AT 2 R activation.…”

Interaction between angiotensin II and relaxin 2 in the progress of growth and spread of prostate cancer cells

“…Interactions between RAS and the relaxin family peptide system have been reported in organ fibrosis (9), blood pressure, in the cardiovascular system (10,11), and osmoregulation, for the central nervous system (12,13) but so far, never in the carcinogenesis of reproductive tissues. However, this study is the first to present the influence of the combined action of angiotensin II and relaxin 2 on various aspects of prostate cancer development and progression.…”

N-acetylcysteine alleviates angiotensin II-mediated renal fibrosis in mouse obstructed kidneys

“…Overactivation of RAS stimulates the proliferation of renal mesangial cells and interstitial fibroblasts, increases the synthesis and secretion of inflammatory factors by renal inherent cells, and promotes the morphological and functional remodeling of cells [6][7][8][9][10][11] . Because angiotensin II (Ang II) is the major effector in RAS, angiotensin-converting enzyme inhibitors (ACEI) and Ang II type I receptor blockers (ARB) are currently recommended as the first-line medications for the treatment of CKD.…”