Anti-fibrotic Potential of AT2 Receptor Agonists

Wang, Yan; Borgo, M; Lee, Huey W.; Baraldi, Dhãniel; Hirmiz, Baydaa; Gaspari, Tracey; Denton, Kate M.; Aguilar, Marie‐Isabel; Samuel, Chrishan S.; Widdop, Robert E

doi:10.3389/fphar.2017.00564

Cited by 62 publications

(63 citation statements)

References 73 publications

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“…Therefore, AT1R-AT2R-RXFP1 complexes and/or functional interactions are most likely to be observed under pathological conditions when components of the RAS are up-regulated. These conditions that display increased Ang II and TGF-1 are precisely those where RLX 8,10,12 and C21 26,27 are known to mediate their anti-fibrotic effects against increased Ang II and TGF-1, whereas these interactions are less likely to occur under physiological conditions.…”

Section: Discussionmentioning

confidence: 99%

“…25 These findings are consistent with the organ protection and inhibition of TGF-1 signal transduction that is mediated by AT2R activation. [26][27][28] Furthermore, they may explain why RLX only affects injury-induced aberrant ECM/collagen deposition without affecting basal matrix turnover, as the AT2R is poorly expressed in healthy adult tissues and cells, but is dramatically up-regulated post-injury or after repeated stimulation and/or inflammation of the kidney and heart. 26,29,30 Along with RXFP1 and the AT2R, the AT1R is also expressed on (myo)fibroblasts 26,31 and mediates the pro-fibrotic and vasoconstrictor actions of Ang II.…”

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confidence: 99%

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AT1R-AT2R-RXFP1 Functional Crosstalk in Myofibroblasts: Impact on the Therapeutic Targeting of Renal and Cardiac Fibrosis

Chow

Kočan

Shen

et al. 2019

JASN

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Background Recombinant human H2 relaxin (serelaxin) has emerged as a potential agent to treat fibrosis, the pathological hallmark of chronic disease. As we now know that serelaxin requires the angiotensin II (Ang II) type 2 receptor (AT2R) to ameliorate renal fibrogenesis in vitro and in vivo, we sought to determine if its anti-fibrotic actions were affected by Ang II type 1 receptor (AT1R) modulation. Methods We examined the signal transduction mechanisms of serelaxin when applied to primary rat renal and human cardiac myofibroblasts in vitro, and in three models of renal-or cardiomyopathy-induced fibrosis in vivo. Results The anti-fibrotic signal transduction of serelaxin via its cognate receptor, relaxin family peptide receptor 1 (RXFP1), was abrogated by the AT1R blockers, irbesartan or candesartan in vitro and in vivo. Candesartan also ameliorated serelaxin's anti-fibrotic actions in the left ventricle of mice with cardiomyopathy, indicating that the inhibitory effects of candesartan were not confined to the kidney. In a transfected cell system, we demonstrated that serelaxin did not directly bind to AT1Rs but that constitutive AT1R-RXFP1 interactions could form. To potentially explain these findings, we also demonstrated that all three receptors were expressed by renal and cardiac (myo)fibroblasts and that antagonists acting at each receptor directly/allosterically blocked the anti-fibrotic effects of either serelaxin or the AT2R agonist, Compound 21. Conclusions These findings have significant implications for the concomitant use of RXFP1 or AT2R agonists with AT1R blockers and suggest that functional AT1R-AT2R-RXFP1 interactions on myofibroblasts may represent new targets for controlling fibrosis progression.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

AT1R-AT2R-RXFP1 Functional Crosstalk in Myofibroblasts: Impact on the Therapeutic Targeting of Renal and Cardiac Fibrosis

Chow

Kočan

Shen

et al. 2019

JASN

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“…Rather, AT 2 R‐agonists are being developed for Idiopathic Pulmonary Fibrosis (IPF) (http://www.vicorepharma.com) and cancer (http://www.morphosys.com); a Mas‐agonist is being developed for Duchenne Muscular Dystrophy (http://www.tarixpharma.com). The clinical development for IPF is based on a number of studies showing therapeutic effects of AT 2 R‐agonists in preclinical models of fibrotic diseases—studies which also identified various anti‐fibrotic mechanisms elicited by this receptor …”

Section: Introductionmentioning

confidence: 99%

Anti‐fibrotic mechanisms of angiotensin AT₂‐receptor stimulation

et al. 2019

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The angiotensin AT 2 -receptor is a main receptor of the protective arm of the renin-angiotensin system. Understanding of this unconventional G-protein coupled receptor has significantly advanced during the past decade, largely because of the availability of a selective non-peptide AT 2 -receptor agonist, which allowed the conduct of a multitude of studies in animal disease models. This article reviews such preclinical studies that in their entirety provide strong evidence for an anti-fibrotic effect mediated by activation of the AT 2 -receptor. Prevention of the development of fibrosis by AT 2 -receptor stimulation has been demonstrated in lungs, heart, blood vessels, kidney, pancreas and skin. In lungs, AT 2 -receptor stimulation was even able to reverse existing fibrosis. The article further discusses intracellular signalling mechanisms mediating the AT 2 -receptor-coupled anti-fibrotic effect, including activation of phosphatases and subsequent interference with pro-fibrotic signalling pathways, induction of matrixmetalloproteinases and hetero-dimerization with the AT 1 -receptor, the TGF-βRII-receptor or the RXFP1-receptor for relaxin. Knowledge of the anti-fibrotic effects of the AT 2 -receptor is of particular relevance because drugs targeting this receptor have entered clinical development for indications involving fibrotic diseases.

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“…Antagonists for either AT 1 R or AT 2 R block relaxin/RXFP1 signaling, supporting comprehensive crosstalk between RXFP1 homodimer and RXFP1‐AT 1 R and RXFP1‐AT 2 R heterodimers (Chow et al, ). In addition, AT 2 R activation reduces TGF‐β1 stimulation of profibrotic pathways (Jones, Vinh, McCarthy, Gaspari, & Widdop, ; Peluso, Santos, Unger, & Steckelings, ; Wang et al, ). The complexity of RXFP1 homo and heterodimerization suggests that RXFP1 is at the center of renal‐specific relaxin/RXFP1 antifibrotic signaling.…”

Section: Rxfp1 and Fibrotic Diseasementioning

confidence: 99%

The relaxin family peptide receptor 1 (RXFP1): An emerging player in human health and disease

Chen

Hung

et al. 2020

Molec Gen & Gen Med

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Background: Relaxin/relaxin family peptide receptor 1 (RXFP1) signaling is important for both normal physiology and disease. Strong preclinical evidence supports relaxin as a potent antifibrotic molecule. However, relaxin-based therapy failed in clinical trial in patients with systemic sclerosis. We and others have discovered that aberrant expression of RXFP1 may contribute to the abnormal relaxin/RXFP1 signaling in different diseases. Reduced RXFP1 expression and alternative splicing transcripts with potential functional consequences have been observed in fibrotic tissues.A relative decrease in RXFP1 expression in fibrotic tissues-specifically lung and skin-may explain a potential insensitivity to relaxin. In addition, receptor dimerization also plays important roles in relaxin/RXFP1 signaling. Methods: This review describes the tissue specific expression, characteristics of the splicing variants, and homo/heterodimerization of RXFP1 in both normal physiological function and human diseases. We discuss the potential implications of these molecular features for developing therapeutics to restore relaxin/RXFP1 signaling and to harness relaxin's potential antifibrotic effects. Results: Relaxin/RXFP1 signaling is important in both normal physiology and in human diseases. Reduced expression of RXFP1 in fibrotic lung and skin tissues surrenders both relaxin/RXFP1 signaling and their responsiveness to exogenous relaxin treatments. Alternative splicing and receptor dimerization are also important in regulating relaxin/RXFP1 signaling. Conclusions: Understanding the molecular mechanisms that drive aberrant expression of RXFP1 in disease and the functional roles of alternative splicing and receptor dimerization will provide insight into therapeutic targets that may restore the relaxin responsiveness of fibrotic tissues. K E Y W O R D S alternative splicing, fibrosis, relaxin, RXFP1While much is known about the cell signaling pathways activated by relaxin, it is clear that ligand-receptor interactions are multidimensional and represent a potential site for cell signaling regulation. In experimental binding assays, relaxin dose, treatment length, and assay temperature contributed to the efficiency of relaxin binding to its receptor (Svendsen

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Anti-fibrotic Potential of AT2 Receptor Agonists

Cited by 62 publications

References 73 publications

AT1R-AT2R-RXFP1 Functional Crosstalk in Myofibroblasts: Impact on the Therapeutic Targeting of Renal and Cardiac Fibrosis

AT1R-AT2R-RXFP1 Functional Crosstalk in Myofibroblasts: Impact on the Therapeutic Targeting of Renal and Cardiac Fibrosis

Anti‐fibrotic mechanisms of angiotensin AT₂‐receptor stimulation

The relaxin family peptide receptor 1 (RXFP1): An emerging player in human health and disease

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Anti-fibrotic Potential of AT2 Receptor Agonists

Cited by 62 publications

References 73 publications

AT1R-AT2R-RXFP1 Functional Crosstalk in Myofibroblasts: Impact on the Therapeutic Targeting of Renal and Cardiac Fibrosis

AT1R-AT2R-RXFP1 Functional Crosstalk in Myofibroblasts: Impact on the Therapeutic Targeting of Renal and Cardiac Fibrosis

Anti‐fibrotic mechanisms of angiotensin AT2‐receptor stimulation

The relaxin family peptide receptor 1 (RXFP1): An emerging player in human health and disease

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Anti‐fibrotic mechanisms of angiotensin AT₂‐receptor stimulation