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

Bryna SM Chow, Martina Kocan, Sanja Bosnyak, Mohsin Sarwar, Belinda Wigg, Emma Susan Jones, Robert E Widdop, Roger J Summers, Ross A D Bathgate, Tim D Hewitson, Chrishan S Samuel

Research output: Contribution to journalArticleResearchpeer-review

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-beta1 (TGF-beta1) 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-beta1 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.
Original languageEnglish
Pages (from-to)75 - 85
Number of pages11
JournalKidney International
Volume86
Issue number1
DOIs
Publication statusPublished - 2014

Cite this

Chow, Bryna SM ; Kocan, Martina ; Bosnyak, Sanja ; Sarwar, Mohsin ; Wigg, Belinda ; Jones, Emma Susan ; Widdop, Robert E ; Summers, Roger J ; Bathgate, Ross A D ; Hewitson, Tim D ; Samuel, Chrishan S. / Relaxin requires the angiotensin II type 2 receptor to abrogate renal interstitial fibrosis. In: Kidney International. 2014 ; Vol. 86, No. 1. pp. 75 - 85.
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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-beta1 (TGF-beta1) 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-beta1 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.",
author = "Chow, {Bryna SM} and Martina Kocan and Sanja Bosnyak and Mohsin Sarwar and Belinda Wigg and Jones, {Emma Susan} 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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Relaxin requires the angiotensin II type 2 receptor to abrogate renal interstitial fibrosis. / Chow, Bryna SM; Kocan, Martina; Bosnyak, Sanja; Sarwar, Mohsin; Wigg, Belinda; Jones, Emma Susan; Widdop, Robert E; Summers, Roger J; Bathgate, Ross A D; Hewitson, Tim D; Samuel, Chrishan S.

In: Kidney International, Vol. 86, No. 1, 2014, p. 75 - 85.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Relaxin requires the angiotensin II type 2 receptor to abrogate renal interstitial fibrosis

AU - Chow, Bryna SM

AU - Kocan, Martina

AU - Bosnyak, Sanja

AU - Sarwar, Mohsin

AU - Wigg, Belinda

AU - Jones, Emma Susan

AU - Widdop, Robert E

AU - Summers, Roger J

AU - Bathgate, Ross A D

AU - Hewitson, Tim D

AU - Samuel, Chrishan S

PY - 2014

Y1 - 2014

N2 - 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-beta1 (TGF-beta1) 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-beta1 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.

AB - 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-beta1 (TGF-beta1) 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-beta1 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.

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JO - Kidney International

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