Functional crosstalk between angiotensin receptors (types 1 and 2) and relaxin family peptide receptor 1 (RXFP1): Implications for the therapeutic targeting of fibrosis

Abstract

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.

Relaxin combined with transarterial chemoembolization achieved synergistic effects and inhibited liver cancer metastasis in a rabbit VX2 model

“…Relaxin (RLX) is a hormone with antifibrotic properties that inhibits profibrotic cytokine-mediated abnormal fibroblast proliferation, differentiation and matrix production by binding to its primary receptor RXFP1 (relaxin family peptide receptor 1) (Zhou et al 2021b ; Samuel et al 2022 ). Previous research have demonstrated that RLX has the ability to upregulate matrix metalloproteinase (MMP), including MMP-2 and MMP-9, and decrease the formation of fibrotic ECM in the treatment of pancreatic cancer and prostate cancer, resulting in positive therapeutic outcomes (Mardhian et al 2018 ; Feng et al 2010 ).…”

Highlights and hot topics in GPCR research from ‘Down Under’

“…While angiotensin II type 1 (AT 1 ) and type 2 (AT 2 ) and relaxin RXFP1 receptors have long been associated with disease progression, there has been little focus on the interplay and functional cross‐talk between these receptors in myofibroblasts. Samuel et al (2024) detail the profibrotic and antifibrotic properties of each receptor, including progress with clinical trials for an AT 2 receptor agonist. They then explore the therapeutic implications for receptor cross‐talk in fibrosis, using the example of reduced efficacy of targeting AT 2 or RXFP 1 when co‐administered with an AT 1 receptor blocker.…”