G Protein–Coupled Receptor-G–Protein βγ–Subunit Signaling Mediates Renal Dysfunction and Fibrosis in Heart Failure

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.

Heart Failure Increases the Risk of Adverse Renal Outcomes in Patients With Normal Kidney Function

“…It is thought that the elevated renal G-Protein Coupled Receptor – G protein βγ (GPCR-Gβγ) signaling and endothelin system expression seen in heart failure may cause renal tissue damage, fibrosis and inflammation, which can manifest as acute renal failure and cardiorenal syndrome 2. 33 …”

Pharmacological and Activated Fibroblast Targeting of Gβγ-GRK2 After Myocardial Ischemia Attenuates Heart Failure Progression

“…Disruption of pathological Gβγ-GRK2 signaling, using various inhibitory peptides (6) and small molecules (7–9), has proven highly successful. We recently demonstrated the therapeutic efficacy of gallein-mediated Gβγ-GRK2 inhibition in cardiorenal syndrome, where it directly attenuated both myocardial and renal dysfunction and fibrosis (16). However, the cellular specificity of this systemic inhibition had not previously been thoroughly investigated, particularly regarding the cardiac fibroblast.…”

Targeting GPCR-Gβγ-GRK2 signaling as a novel strategy for treating cardiorenal pathologies

“…Considering the role of GPCR signaling in normal physiology and pathology of both heart and kidney, we recently scrutinized the role of GPCR-Gβγ-GRK2 in CRS type 2 (CRS2), which is characterized as a chronic heart failure (CHF) accompanied by the development of CKD [123] and [127]. The study proposed that elevated activity of SNS and endothelin (ET) system causes desensitization and down-regulation of renal GPCRs owing to pathologic Gβγ-GRK2 interactions, resembling the dysregulation of β-ARs observed in HF.…”

“…Moreover, the study provides mechanistic insight into fibrotic tissue remodeling, demonstrating the role of Gβγ signaling in mouse embryonic fibroblasts (MEFs) endothelin-1 induced activation and migration [127] and [129]. …”