G Protein-Coupled Receptor-G-Protein βγ-Subunit Signaling Mediates Renal Dysfunction and Fibrosis in Heart Failure
Copyright © 2016 by the American Society of Nephrology..
Development of CKD secondary to chronic heart failure (CHF), known as cardiorenal syndrome type 2 (CRS2), clinically associates with organ failure and reduced survival. Heart and kidney damage in CRS2 results predominantly from chronic stimulation of G protein-coupled receptors (GPCRs), including adrenergic and endothelin (ET) receptors, after elevated neurohormonal signaling of the sympathetic nervous system and the downstream ET system, respectively. Although we and others have shown that chronic GPCR stimulation and the consequent upregulated interaction between the G-protein βγ-subunit (Gβγ), GPCR-kinase 2, and β-arrestin are central to various cardiovascular diseases, the role of such alterations in kidney diseases remains largely unknown. We investigated the possible salutary effect of renal GPCR-Gβγ inhibition in CKD developed in a clinically relevant murine model of nonischemic hypertrophic CHF, transverse aortic constriction (TAC). By 12 weeks after TAC, mice developed CKD secondary to CHF associated with elevated renal GPCR-Gβγ signaling and ET system expression. Notably, systemic pharmacologic Gβγ inhibition by gallein, which we previously showed alleviates CHF in this model, attenuated these pathologic renal changes. To investigate a direct effect of gallein on the kidney, we used a bilateral ischemia-reperfusion AKI mouse model, in which gallein attenuated renal dysfunction, tissue damage, fibrosis, inflammation, and ET system activation. Furthermore, in vitro studies showed a key role for ET receptor-Gβγ signaling in pathologic fibroblast activation. Overall, our data support a direct role for GPCR-Gβγ in AKI and suggest GPCR-Gβγ inhibition as a novel therapeutic approach for treating CRS2 and AKI.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2017 |
---|---|
Erschienen: |
2017 |
Enthalten in: |
Zur Gesamtaufnahme - volume:28 |
---|---|
Enthalten in: |
Journal of the American Society of Nephrology : JASN - 28(2017), 1 vom: 14. Jan., Seite 197-208 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Kamal, Fadia A [VerfasserIn] |
---|
Links: |
---|
Anmerkungen: |
Date Completed 02.06.2017 Date Revised 13.11.2018 published: Print-Electronic Citation Status MEDLINE |
---|
doi: |
10.1681/ASN.2015080852 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM261360620 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM261360620 | ||
003 | DE-627 | ||
005 | 20231224195405.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231224s2017 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1681/ASN.2015080852 |2 doi | |
028 | 5 | 2 | |a pubmed24n0871.xml |
035 | |a (DE-627)NLM261360620 | ||
035 | |a (NLM)27297948 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Kamal, Fadia A |e verfasserin |4 aut | |
245 | 1 | 0 | |a G Protein-Coupled Receptor-G-Protein βγ-Subunit Signaling Mediates Renal Dysfunction and Fibrosis in Heart Failure |
264 | 1 | |c 2017 | |
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 02.06.2017 | ||
500 | |a Date Revised 13.11.2018 | ||
500 | |a published: Print-Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a Copyright © 2016 by the American Society of Nephrology. | ||
520 | |a Development of CKD secondary to chronic heart failure (CHF), known as cardiorenal syndrome type 2 (CRS2), clinically associates with organ failure and reduced survival. Heart and kidney damage in CRS2 results predominantly from chronic stimulation of G protein-coupled receptors (GPCRs), including adrenergic and endothelin (ET) receptors, after elevated neurohormonal signaling of the sympathetic nervous system and the downstream ET system, respectively. Although we and others have shown that chronic GPCR stimulation and the consequent upregulated interaction between the G-protein βγ-subunit (Gβγ), GPCR-kinase 2, and β-arrestin are central to various cardiovascular diseases, the role of such alterations in kidney diseases remains largely unknown. We investigated the possible salutary effect of renal GPCR-Gβγ inhibition in CKD developed in a clinically relevant murine model of nonischemic hypertrophic CHF, transverse aortic constriction (TAC). By 12 weeks after TAC, mice developed CKD secondary to CHF associated with elevated renal GPCR-Gβγ signaling and ET system expression. Notably, systemic pharmacologic Gβγ inhibition by gallein, which we previously showed alleviates CHF in this model, attenuated these pathologic renal changes. To investigate a direct effect of gallein on the kidney, we used a bilateral ischemia-reperfusion AKI mouse model, in which gallein attenuated renal dysfunction, tissue damage, fibrosis, inflammation, and ET system activation. Furthermore, in vitro studies showed a key role for ET receptor-Gβγ signaling in pathologic fibroblast activation. Overall, our data support a direct role for GPCR-Gβγ in AKI and suggest GPCR-Gβγ inhibition as a novel therapeutic approach for treating CRS2 and AKI | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a GPCR-g protein signaling | |
650 | 4 | |a acute renal failure | |
650 | 4 | |a chronic heart failure | |
650 | 4 | |a chronic kidney disease | |
650 | 4 | |a renal fibrosis | |
650 | 7 | |a G-protein Beta gamma |2 NLM | |
650 | 7 | |a GTP-Binding Protein beta Subunits |2 NLM | |
650 | 7 | |a GTP-Binding Protein gamma Subunits |2 NLM | |
650 | 7 | |a Receptors, G-Protein-Coupled |2 NLM | |
700 | 1 | |a Travers, Joshua G |e verfasserin |4 aut | |
700 | 1 | |a Schafer, Allison E |e verfasserin |4 aut | |
700 | 1 | |a Ma, Qing |e verfasserin |4 aut | |
700 | 1 | |a Devarajan, Prasad |e verfasserin |4 aut | |
700 | 1 | |a Blaxall, Burns C |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Journal of the American Society of Nephrology : JASN |d 1990 |g 28(2017), 1 vom: 14. Jan., Seite 197-208 |w (DE-627)NLM012606502 |x 1533-3450 |7 nnns |
773 | 1 | 8 | |g volume:28 |g year:2017 |g number:1 |g day:14 |g month:01 |g pages:197-208 |
856 | 4 | 0 | |u http://dx.doi.org/10.1681/ASN.2015080852 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 28 |j 2017 |e 1 |b 14 |c 01 |h 197-208 |