Relaxin requires the angiotensin II type 2 receptor to abrogate renal interstitial fibrosis
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.
| Errataetall: | |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2014 |
|---|---|
| Erschienen: |
2014 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:86 |
|---|---|
| Enthalten in: |
Kidney international - 86(2014), 1 vom: 15. Juli, Seite 75-85 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Chow, Bryna S Man [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 02.05.2016 Date Revised 09.12.2020 published: Print-Electronic CommentIn: Kidney Int. 2014 Jul;86(1):9-10. - PMID 24978374 Citation Status MEDLINE |
|---|
| doi: |
10.1038/ki.2013.518 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM234526238 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM234526238 | ||
| 003 | DE-627 | ||
| 005 | 20231224101444.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231224s2014 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/ki.2013.518 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0781.xml |
| 035 | |a (DE-627)NLM234526238 | ||
| 035 | |a (NLM)24429402 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Chow, Bryna S Man |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Relaxin requires the angiotensin II type 2 receptor to abrogate renal interstitial fibrosis |
| 264 | 1 | |c 2014 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 02.05.2016 | ||
| 500 | |a Date Revised 09.12.2020 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: Kidney Int. 2014 Jul;86(1):9-10. - PMID 24978374 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Angiotensin II Type 2 Receptor Blockers |2 NLM | |
| 650 | 7 | |a Imidazoles |2 NLM | |
| 650 | 7 | |a Pyridines |2 NLM | |
| 650 | 7 | |a RLN2 protein, human |2 NLM | |
| 650 | 7 | |a RXFP1 protein, mouse |2 NLM | |
| 650 | 7 | |a Receptor, Angiotensin, Type 2 |2 NLM | |
| 650 | 7 | |a Receptors, G-Protein-Coupled |2 NLM | |
| 650 | 7 | |a Receptors, Peptide |2 NLM | |
| 650 | 7 | |a Recombinant Proteins |2 NLM | |
| 650 | 7 | |a Rxfp1 protein, rat |2 NLM | |
| 650 | 7 | |a Transforming Growth Factor beta1 |2 NLM | |
| 650 | 7 | |a PD 123319 |2 NLM | |
| 650 | 7 | |a 130663-39-7 |2 NLM | |
| 650 | 7 | |a Relaxin |2 NLM | |
| 650 | 7 | |a 9002-69-1 |2 NLM | |
| 700 | 1 | |a Kocan, Martina |e verfasserin |4 aut | |
| 700 | 1 | |a Bosnyak, Sanja |e verfasserin |4 aut | |
| 700 | 1 | |a Sarwar, Mohsin |e verfasserin |4 aut | |
| 700 | 1 | |a Wigg, Belinda |e verfasserin |4 aut | |
| 700 | 1 | |a Jones, Emma S |e verfasserin |4 aut | |
| 700 | 1 | |a Widdop, Robert E |e verfasserin |4 aut | |
| 700 | 1 | |a Summers, Roger J |e verfasserin |4 aut | |
| 700 | 1 | |a Bathgate, Ross A D |e verfasserin |4 aut | |
| 700 | 1 | |a Hewitson, Tim D |e verfasserin |4 aut | |
| 700 | 1 | |a Samuel, Chrishan S |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Kidney international |d 1972 |g 86(2014), 1 vom: 15. Juli, Seite 75-85 |w (DE-627)NLM000007188 |x 1523-1755 |7 nnns |
| 773 | 1 | 8 | |g volume:86 |g year:2014 |g number:1 |g day:15 |g month:07 |g pages:75-85 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/ki.2013.518 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 86 |j 2014 |e 1 |b 15 |c 07 |h 75-85 | ||