Abstract 17562: GPCR Gβγ Signaling Mediates Renal Dysfunction and Fibrosis in Heart Failure Mice
Background: Cardiorenal syndrome type 2 (CRS2), the development of chronic kidney disease (CKD) secondary to chronic heart failure (CHF), is clinically associated with increased incidence of organ failure and reduced survival. Heart and kidney damage in CRS2 is greatly caused by chronic stimulation of the adrenergic and endothelin receptors as a result of elevated neurohormonal signaling of the sympathetic nervous system (SNS) and its downstream endothelin (ET) system, respectively. These receptors belong to the superfamily of G protein-coupled receptors (GPCRs). While chronic GPCR stimulation and its associated upregulated interaction between the G-protein βγ subunit (Gβγ), the GPCR-kinase 2 (GRK2) and β-arrestin are known to be central to various cardiovascular diseases, their role in kidney diseases are by far unknown and beg investigation.
Objective: CRS2 animal studies utilize combine ischemic cardiac injury and renal injury, which is of poor clinical relevance. Our study investigates: (1) the development of chronic kidney disease (CKD) in a model of non-ischemic CHF without inducing surgical kidney injury, aiming to establish a more clinically relevant CRS2 model. (2) The possible salutary effect of renal GPCR-Gβγ inhibition in CKD developed in the established CRS2 model.
Methods and results: We utilized transverse aortic constriction (TAC) as a non-ischemic hypertrophic murine CHF model. Twelve weeks after TAC, mice developed CKD secondary to CHF suggesting a CRS2 model. This was associated with elevated renal GPCR-Gβγ signaling and ET system expression. Importantly, systemic pharmacologic Gβγ inhibition by gallein attenuated these renal pathological changes in parallel with alleviated CHF. A direct effect of gallein on the kidney was subsequently confirmed in a bilateral ischemia reperfusion acute kidney injury (AKI) mouse model where it attenuated renal dysfunction, tissue damage and ET system activation, indicating a direct role for GPCR-Gβγ signaling in AKI. Further, in vitro studies in mouse embryonic fibroblasts showed a key role for ET receptor-Gβγ signaling in fibroblast activation.
Conclusion: Our data suggest TAC as a clinically relevant CRS2 model and GPCR-Gβγ inhibition as a novel therapeutic approach for CRS2 and AKI.
Author Disclosures: F.A. Kamal: None. J.G. Travers: None. A.E. Schafer: None. Q. Ma: None. P. Devarajan: None. B.C. Blaxall: None.
- © 2015 by American Heart Association, Inc.