G Protein-Coupled Receptor-G-Protein ßγ-Subunit Signaling Mediates Renal Dysfunction and Fibrosis in Heart Failure.
J Am Soc Nephrol
; 28(1): 197-208, 2017 Jan.
Article
en En
| MEDLINE
| ID: mdl-27297948
ABSTRACT
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 ßγ-subunit (Gßγ), GPCR-kinase 2, and ß-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-Gßγ 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-Gßγ signaling and ET system expression. Notably, systemic pharmacologic Gßγ 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-Gßγ signaling in pathologic fibroblast activation. Overall, our data support a direct role for GPCR-Gßγ in AKI and suggest GPCR-Gßγ inhibition as a novel therapeutic approach for treating CRS2 and AKI.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Subunidades beta de la Proteína de Unión al GTP
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Subunidades gamma de la Proteína de Unión al GTP
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Receptores Acoplados a Proteínas G
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Síndrome Cardiorrenal
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Insuficiencia Cardíaca
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Riñón
Tipo de estudio:
Etiology_studies
Límite:
Animals
Idioma:
En
Año:
2017
Tipo del documento:
Article