AT1R-AT2R-RXFP1 functional crosstalk in myofibroblasts

Impact on the therapeutic targeting of renal and cardiac fibrosis

Bryna S. M. Chow, Martina Kocan, Matthew Shen, Yan Wang, Lei Han, Jacqueline Y. Chew, Chao Wang, Sanja Bosnyak, Katrina M. Mirabito-Colafella, Giannie Barsha, Belinda Wigg, Elizabeth K. M. Johnstone, Mohammed A. Hossain, Kevin D. G. Pfleger, Kate M. Denton, Robert E. Widdop, Roger J. Summers, Ross A. D. Bathgate, Tim D. Hewitson, Chrishan S. Samuel

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background Recombinant human relaxin-2 (serelaxin), which has organ-protective actions mediated via its cognate G protein–coupled receptor relaxin family peptide receptor 1 (RXFP1), has emerged as a potential agent to treat fibrosis. Studies have shown that serelaxin requires the angiotensin II (AngII) type 2 receptor (AT2R) to ameliorate renal fibrogenesis in vitro and in vivo. Whether its antifibrotic actions are affected by modulation of the AngII type 1 receptor (AT1R), which is expressed on myofibroblasts along with RXFP1 and AT2R, is unknown.
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 AT1R blockers irbesartan and candesartan abrogated antifibrotic signal transduction of serelaxin via RXFP1 in vitro and in vivo. Candesartan also ameliorated serelaxin’s antifibrotic actions in the left ventricle of mice with cardiomyopathy, indicating that candesartan’s inhibitory effects were not confined to the kidney. We also demonstrated in a transfected cell system 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 renal and cardiac myofibroblasts expressed all three receptors and that antagonists acting at each receptor directly or allosterically blocked the antifibrotic effects of either serelaxin or an 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 interactions between the three receptors on myofibroblasts may represent new targets for controlling fibrosis progression.
Original languageEnglish
Pages (from-to)2191-2207
Number of pages17
JournalJournal of the American Society of Nephrology
Volume30
Issue number11
DOIs
Publication statusPublished - 1 Jan 2019

Cite this

Chow, Bryna S. M. ; Kocan, Martina ; Shen, Matthew ; Wang, Yan ; Han, Lei ; Chew, Jacqueline Y. ; Wang, Chao ; Bosnyak, Sanja ; Mirabito-Colafella, Katrina M. ; Barsha, Giannie ; Wigg, Belinda ; Johnstone, Elizabeth K. M. ; Hossain, Mohammed A. ; Pfleger, Kevin D. G. ; Denton, Kate M. ; Widdop, Robert E. ; Summers, Roger J. ; Bathgate, Ross A. D. ; Hewitson, Tim D. ; Samuel, Chrishan S. / AT1R-AT2R-RXFP1 functional crosstalk in myofibroblasts : Impact on the therapeutic targeting of renal and cardiac fibrosis. In: Journal of the American Society of Nephrology. 2019 ; Vol. 30, No. 11. pp. 2191-2207.
@article{2b87393a244c4ad484bc3abb2536a434,
title = "AT1R-AT2R-RXFP1 functional crosstalk in myofibroblasts: Impact on the therapeutic targeting of renal and cardiac fibrosis",
abstract = "Background Recombinant human relaxin-2 (serelaxin), which has organ-protective actions mediated via its cognate G protein–coupled receptor relaxin family peptide receptor 1 (RXFP1), has emerged as a potential agent to treat fibrosis. Studies have shown that serelaxin requires the angiotensin II (AngII) type 2 receptor (AT2R) to ameliorate renal fibrogenesis in vitro and in vivo. Whether its antifibrotic actions are affected by modulation of the AngII type 1 receptor (AT1R), which is expressed on myofibroblasts along with RXFP1 and AT2R, is unknown.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 AT1R blockers irbesartan and candesartan abrogated antifibrotic signal transduction of serelaxin via RXFP1 in vitro and in vivo. Candesartan also ameliorated serelaxin’s antifibrotic actions in the left ventricle of mice with cardiomyopathy, indicating that candesartan’s inhibitory effects were not confined to the kidney. We also demonstrated in a transfected cell system 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 renal and cardiac myofibroblasts expressed all three receptors and that antagonists acting at each receptor directly or allosterically blocked the antifibrotic effects of either serelaxin or an 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 interactions between the three receptors on myofibroblasts may represent new targets for controlling fibrosis progression.",
author = "Chow, {Bryna S. M.} and Martina Kocan and Matthew Shen and Yan Wang and Lei Han and Chew, {Jacqueline Y.} and Chao Wang and Sanja Bosnyak and Mirabito-Colafella, {Katrina M.} and Giannie Barsha and Belinda Wigg and Johnstone, {Elizabeth K. M.} and Hossain, {Mohammed A.} and Pfleger, {Kevin D. G.} and Denton, {Kate M.} and Widdop, {Robert E.} and Summers, {Roger J.} and Bathgate, {Ross A. D.} and Hewitson, {Tim D.} and Samuel, {Chrishan S.}",
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language = "English",
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AT1R-AT2R-RXFP1 functional crosstalk in myofibroblasts : Impact on the therapeutic targeting of renal and cardiac fibrosis. / Chow, Bryna S. M.; Kocan, Martina; Shen, Matthew; Wang, Yan; Han, Lei; Chew, Jacqueline Y.; Wang, Chao; Bosnyak, Sanja; Mirabito-Colafella, Katrina M.; Barsha, Giannie; Wigg, Belinda; Johnstone, Elizabeth K. M.; Hossain, Mohammed A.; Pfleger, Kevin D. G.; Denton, Kate M.; Widdop, Robert E.; Summers, Roger J.; Bathgate, Ross A. D.; Hewitson, Tim D.; Samuel, Chrishan S.

In: Journal of the American Society of Nephrology, Vol. 30, No. 11, 01.01.2019, p. 2191-2207.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - AT1R-AT2R-RXFP1 functional crosstalk in myofibroblasts

T2 - Impact on the therapeutic targeting of renal and cardiac fibrosis

AU - Chow, Bryna S. M.

AU - Kocan, Martina

AU - Shen, Matthew

AU - Wang, Yan

AU - Han, Lei

AU - Chew, Jacqueline Y.

AU - Wang, Chao

AU - Bosnyak, Sanja

AU - Mirabito-Colafella, Katrina M.

AU - Barsha, Giannie

AU - Wigg, Belinda

AU - Johnstone, Elizabeth K. M.

AU - Hossain, Mohammed A.

AU - Pfleger, Kevin D. G.

AU - Denton, Kate M.

AU - Widdop, Robert E.

AU - Summers, Roger J.

AU - Bathgate, Ross A. D.

AU - Hewitson, Tim D.

AU - Samuel, Chrishan S.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background Recombinant human relaxin-2 (serelaxin), which has organ-protective actions mediated via its cognate G protein–coupled receptor relaxin family peptide receptor 1 (RXFP1), has emerged as a potential agent to treat fibrosis. Studies have shown that serelaxin requires the angiotensin II (AngII) type 2 receptor (AT2R) to ameliorate renal fibrogenesis in vitro and in vivo. Whether its antifibrotic actions are affected by modulation of the AngII type 1 receptor (AT1R), which is expressed on myofibroblasts along with RXFP1 and AT2R, is unknown.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 AT1R blockers irbesartan and candesartan abrogated antifibrotic signal transduction of serelaxin via RXFP1 in vitro and in vivo. Candesartan also ameliorated serelaxin’s antifibrotic actions in the left ventricle of mice with cardiomyopathy, indicating that candesartan’s inhibitory effects were not confined to the kidney. We also demonstrated in a transfected cell system 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 renal and cardiac myofibroblasts expressed all three receptors and that antagonists acting at each receptor directly or allosterically blocked the antifibrotic effects of either serelaxin or an 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 interactions between the three receptors on myofibroblasts may represent new targets for controlling fibrosis progression.

AB - Background Recombinant human relaxin-2 (serelaxin), which has organ-protective actions mediated via its cognate G protein–coupled receptor relaxin family peptide receptor 1 (RXFP1), has emerged as a potential agent to treat fibrosis. Studies have shown that serelaxin requires the angiotensin II (AngII) type 2 receptor (AT2R) to ameliorate renal fibrogenesis in vitro and in vivo. Whether its antifibrotic actions are affected by modulation of the AngII type 1 receptor (AT1R), which is expressed on myofibroblasts along with RXFP1 and AT2R, is unknown.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 AT1R blockers irbesartan and candesartan abrogated antifibrotic signal transduction of serelaxin via RXFP1 in vitro and in vivo. Candesartan also ameliorated serelaxin’s antifibrotic actions in the left ventricle of mice with cardiomyopathy, indicating that candesartan’s inhibitory effects were not confined to the kidney. We also demonstrated in a transfected cell system 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 renal and cardiac myofibroblasts expressed all three receptors and that antagonists acting at each receptor directly or allosterically blocked the antifibrotic effects of either serelaxin or an 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 interactions between the three receptors on myofibroblasts may represent new targets for controlling fibrosis progression.

UR - http://www.scopus.com/inward/record.url?scp=85074378624&partnerID=8YFLogxK

U2 - 10.1681/ASN.2019060597

DO - 10.1681/ASN.2019060597

M3 - Article

VL - 30

SP - 2191

EP - 2207

JO - Journal of the American Society of Nephrology

JF - Journal of the American Society of Nephrology

SN - 1046-6673

IS - 11

ER -