Protein-coupled receptor-G-protein βγ-subunit signaling mediates renal dysfunction and fibrosis in heart failure

Fadia A. Kamal, Joshua G. Travers, Allison E. Schafer, Qing Ma, Prasad Devarajan, Burns C. Blaxall

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Development ofCKDsecondary 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 systemand the downstream ET system, respectively. Although we and others have shown that chronic GPCR stimulation and the consequent upregulated interaction between the G-protein bg-subunit (Gβγ), GPCR-kinase 2, and b-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 renalGPCR- 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 AKImousemodel, inwhich gallein attenuated renal dysfunction, tissue damage, fibrosis, inflammation, and ET systemactivation. 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.

Original languageEnglish (US)
Pages (from-to)197-208
Number of pages12
JournalJournal of the American Society of Nephrology
Volume28
Issue number1
DOIs
StatePublished - Jan 2017

All Science Journal Classification (ASJC) codes

  • Nephrology

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