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G Protein-Coupled Receptor-G-Protein βγ-Subunit Signaling Mediates Renal Dysfunction and Fibrosis in Heart Failure
Fadia A Kamal1, Joshua G Travers1, Allison E Schafer1
1The Heart Institute, Molecular Cardiovascular Biology and.
Insights
Targeting G protein-coupled receptor (GPCR)-Gβγ signaling with gallein may treat cardiorenal syndrome type 2 (CRS2) and acute kidney injury (AKI). This approach reduces kidney damage and fibrosis by inhibiting GPCR-Gβγ signaling and the endothelin system.
Area of Science:
- Cardiorenal Medicine
- Molecular Pharmacology
- Nephrology
Background:
- Cardiorenal syndrome type 2 (CRS2), characterized by chronic kidney disease (CKD) secondary to chronic heart failure (CHF), is linked to poor outcomes.
- Elevated neurohormonal signaling, particularly sympathetic nervous system and endothelin (ET) system activation, drives heart and kidney damage in CRS2.
- The role of G protein-coupled receptor (GPCR) signaling, specifically G-protein βγ-subunit (Gβγ) interactions, in kidney disease pathogenesis is not well understood.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting renal GPCR-Gβγ signaling in a murine model of CKD secondary to CHF.
- To determine the direct effects of GPCR-Gβγ inhibition on kidney injury and fibrosis using an acute kidney injury (AKI) model.
- To elucidate the role of ET receptor-Gβγ signaling in fibroblast activation.
Main Methods:
- Utilized a transverse aortic constriction (TAC) mouse model to induce nonischemic hypertrophic CHF and subsequent CKD.
- Administered systemic gallein, a pharmacologic Gβγ inhibitor, and assessed renal pathology, GPCR-Gβγ signaling, and ET system expression.
- Employed a bilateral ischemia-reperfusion (I/R) mouse model of AKI and conducted in vitro studies on fibroblast activation.
Main Results:
- TAC-induced CKD mice exhibited elevated renal GPCR-Gβγ signaling and ET system expression.
- Systemic gallein treatment attenuated renal dysfunction, tissue damage, fibrosis, and inflammation in both CHF-CKD and I/R-AKI models.
- Gallein inhibited ET system activation and ET receptor-Gβγ signaling in fibroblast activation.
Conclusions:
- GPCR-Gβγ signaling plays a direct role in the pathogenesis of AKI.
- Pharmacologic inhibition of GPCR-Gβγ signaling, as demonstrated with gallein, offers a potential therapeutic strategy for CRS2.
- Targeting GPCR-Gβγ signaling presents a novel therapeutic avenue for treating cardiorenal syndromes and acute kidney injury.
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 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.
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