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G Protein-Coupled Receptor-G-Protein ??-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 ??-subunit (G??), GPCR-kinase 2, and ?-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-G?? 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-G?? signaling and ET system expression. Notably, systemic pharmacologic G?? 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-G?? signaling in pathologic fibroblast activation. Overall, our data support a direct role for GPCR-G?? in AKI and suggest GPCR-G?? inhibition as a novel therapeutic approach for treating CRS2 and AKI.

SUBMITTER: Kamal FA

PROVIDER: S-EPMC5198268 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Kamal Fadia A FA Travers Joshua G JG Schafer Allison E AE Ma Qing Q Devarajan Prasad P Blaxall Burns C BC

Journal of the American Society of Nephrology : JASN 20160613 1

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 chro ...[more]

PMID: 27297948

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Project description:The aim of the present study was to determine if renal sympathetic denervation (RSD) may alleviate isoproterenol-induced left ventricle remodeling, and to identify the underlying mechanism. A total of 70 rats were randomly divided into control (n=15), sham operation (n=15), heart failure (HF) with sham operation (HF + sham; n=20) and HF with treatment (HF + RSD; n=20) groups. The HF model was established by subcutaneous injection of isoproterenol; six weeks later, 1eft ventricular internal diameter at end?systole (LVIDs), left ventricular systolic posterior wall thickness (LVPWs), 1eft ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were measured. Plasma norepinephrine (NE), angiotensin II (Ang II) and aldosterone (ALD) levels were measured by ELISA. Myocardial collagen volume fraction (CVF) was determined by Masson's staining. Reverse transcription?quantitative polymerase chain reaction was used to determine the mRNA expression levels of ventricular transforming growth factor?? (TGF??), connective tissue growth factor (CTGF) and microRNAs (miRs), including miR?29b, miR?30c and miR?133a. The results demonstrated that LVIDs and LVPWs in the HF + RSD group were significantly decreased compared with the HF + sham group. By contrast, LVFS and LVEF in the HF + RSD group were significantly increased compared with the HF + sham group. RSD significantly reduced the levels of plasma NE, Ang II and ALD. CVF in the HF + RSD group was reduced by 38.1% compared with the HF + sham group. Expression levels of TGF?? and CTGF were decreased, whereas those of miR?29b, miR?30c and miR?133a were increased, in the HF + RSD group compared with the HF + sham group. These results indicated that RSD alleviates isoproterenol?induced left ventricle remodeling potentially via downregulation of TGF??/CTGF and upregulation of miR?29b, miR?30c and miR?133a. RSD may therefore be an effective non?drug therapy for the treatment of heart failure.

Project description:IMPORTANCE:Small studies suggest that low-dose dopamine or low-dose nesiritide may enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction; however, neither strategy has been rigorously tested. OBJECTIVE:To test the 2 independent hypotheses that, compared with placebo, addition of low-dose dopamine (2 ?g/kg/min) or low-dose nesiritide (0.005 ?g/kg/min without bolus) to diuretic therapy will enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction. DESIGN, SETTING, AND PARTICIPANTS:Multicenter, double-blind, placebo-controlled clinical trial (Renal Optimization Strategies Evaluation [ROSE]) of 360 hospitalized patients with acute heart failure and renal dysfunction (estimated glomerular filtration rate of 15-60 mL/min/1.73 m2), randomized within 24 hours of admission. Enrollment occurred from September 2010 to March 2013 across 26 sites in North America. INTERVENTIONS:Participants were randomized in an open, 1:1 allocation ratio to the dopamine or nesiritide strategy. Within each strategy, participants were randomized in a double-blind, 2:1 ratio to active treatment or placebo. The dopamine (n?=?122) and nesiritide (n?=?119) groups were independently compared with the pooled placebo group (n?=?119). MAIN OUTCOMES AND MEASURES:Coprimary end points included 72-hour cumulative urine volume (decongestion end point) and the change in serum cystatin C from enrollment to 72 hours (renal function end point). RESULTS:Compared with placebo, low-dose dopamine had no significant effect on 72-hour cumulative urine volume (dopamine, 8524 mL; 95% CI, 7917-9131 vs placebo, 8296 mL; 95% CI, 7762-8830 ; difference, 229 mL; 95% CI, -714 to 1171 mL; P?=?.59) or on the change in cystatin C level (dopamine, 0.12 mg/L; 95% CI, 0.06-0.18 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, 0.01; 95% CI, -0.08 to 0.10; P?=?.72). Similarly, low-dose nesiritide had no significant effect on 72-hour cumulative urine volume (nesiritide, 8574 mL; 95% CI, 8014-9134 vs placebo, 8296 mL; 95% CI, 7762-8830; difference, 279 mL; 95% CI, -618 to 1176 mL; P?=?.49) or on the change in cystatin C level (nesiritide, 0.07 mg/L; 95% CI, 0.01-0.13 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, -0.04; 95% CI, -0.13 to 0.05; P?=?.36). Compared with placebo, there was no effect of low-dose dopamine or nesiritide on secondary end points reflective of decongestion, renal function, or clinical outcomes. CONCLUSION AND RELEVANCE:In participants with acute heart failure and renal dysfunction, neither low-dose dopamine nor low-dose nesiritide enhanced decongestion or improved renal function when added to diuretic therapy. TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT01132846.

Dataset Information

G Protein-Coupled Receptor-G-Protein ??-Subunit Signaling Mediates Renal Dysfunction and Fibrosis in Heart Failure.

Publications

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

Similar Datasets

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