GRK2-Mediated Crosstalk Between β-Adrenergic and Angiotensin II Receptors Enhances Adrenocortical Aldosterone Production In Vitro and In Vivo

Pollard, Celina M; Ghandour, Jennifer; Cora, Natalie; Perez, Arianna; Parker, Barbara M; Desimine, Victoria L; Wertz, Shelby L; Pereyra, Janelle M; Ferraino, Krysten E; Patel, Jainika J; Lymperopoulos, Anastasios

doi:10.3390/ijms21020574

Cited by 12 publications

(7 citation statements)

References 36 publications

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“…Renal fibrosis is a complicated disorder characterized by the destruction of kidney parenchyma, composed by the abnormal accumulation of ECM and lower glomerular filtration rate (114). GRK2 plays a canonical role in regulating angiotensin II type 1 receptor (AT1R) desensitization, which is important in modulating a multitude of function in the kidney such as renal blood flow, glomerular filtration (115). GRK2 knockout rat model has been used to investigate the effects of GRK2 in kidney diseases, continues studies investigate that severer kidney-specific damage was occurred in GRK2 knockdown mice.…”

Section: Renal Fibrosismentioning

confidence: 99%

G Protein-Coupled Receptor Kinase 2 as Novel Therapeutic Target in Fibrotic Diseases

Shan

et al. 2022

Front. Immunol.

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G protein-coupled receptor kinase 2 (GRK2), an important subtype of GRKs, specifically phosphorylates agonist-activated G protein-coupled receptors (GPCRs). Besides, current research confirms that it participates in multiple regulation of diverse cells via a non-phosphorylated pathway, including interacting with various non-receptor substrates and binding partners. Fibrosis is a common pathophysiological phenomenon in the repair process of many tissues due to various pathogenic factors such as inflammation, injury, drugs, etc. The characteristics of fibrosis are the activation of fibroblasts leading to myofibroblast proliferation and differentiation, subsequent aggerate excessive deposition of extracellular matrix (ECM). Then, a positive feedback loop is occurred between tissue stiffness caused by ECM and fibroblasts, ultimately resulting in distortion of organ architecture and function. At present, GRK2, which has been described as a multifunctional protein, regulates copious signaling pathways under pathophysiological conditions correlated with fibrotic diseases. Along with GRK2-mediated regulation, there are diverse effects on the growth and apoptosis of different cells, inflammatory response and deposition of ECM, which are essential in organ fibrosis progression. This review is to highlight the relationship between GRK2 and fibrotic diseases based on recent research. It is becoming more convincing that GRK2 could be considered as a potential therapeutic target in many fibrotic diseases.

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Section: Renal Fibrosismentioning

confidence: 99%

G Protein-Coupled Receptor Kinase 2 as Novel Therapeutic Target in Fibrotic Diseases

Shan

et al. 2022

Front. Immunol.

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“…The H9c2 rat cardiomyoblast cell line was purchased from American Type Culture Collection (Manassas, VA, United States) and cultured as previously described[ 11 , 16 - 18 ]. Recombinant lentiviruses encoding for wild-type full-length GRK5 or for empty vector (control) (OriGene Technologies, Rockville, MD, United States) were propagated and purified via CsCl density gradient ultracentrifugation, as described previously[ 11 , 19 ]. For CRISPR/Cas9-mediated GRK5 gene deletion, a gRNA sequence was custom-synthesized by Sigma-Aldrich (target ID: RN0000391809, target sequence: 5’-GTGGTTTGAATTTATGCGG-3’) and incorporated into a lentiviral vector (Sigma-Aldrich).…”

Section: Methodsmentioning

confidence: 99%

GRK5 is an essential co-repressor of the cardiac mineralocorticoid receptor and is selectively induced by finerenone

Pollard¹,

Suster²,

Cora³

et al. 2022

WJC

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BACKGROUND In the heart, aldosterone (Aldo) binds the mineralocorticoid receptor (MR) to exert damaging, adverse remodeling-promoting effects. We recently showed that G protein-coupled receptor-kinase (GRK)-5 blocks the cardiac MR by directly phosphorylating it, thereby repressing its transcriptional activity. MR antagonist (MRA) drugs block the cardiac MR reducing morbidity and mortality of advanced human heart failure. Non-steroidal MRAs, such as finerenone, may provide better cardio-protection against Aldo than classic, steroidal MRAs, like spironolactone and eplerenone. AIM To investigate potential differences between finerenone and eplerenone at engaging GRK5-dependent cardiac MR phosphorylation and subsequent blockade. METHODS We used H9c2 cardiomyocytes, which endogenously express the MR and GRK5. RESULTS GRK5 phosphorylates the MR in H9c2 cardiomyocytes in response to finerenone but not to eplerenone. Unlike eplerenone, finerenone alone potently and efficiently suppresses cardiac MR transcriptional activity, thus displaying inverse agonism. GRK5 is necessary for finerenone’s inverse agonism, since GRK5 genetic deletion renders finerenone incapable of blocking cardiac MR transcriptional activity. Eplerenone alone does not fully suppress cardiac MR basal activity regardless of GRK5 expression levels. Finally, GRK5 is necessary for the anti-apoptotic, anti-oxidative, and anti-fibrotic effects of both finerenone and eplerenone against Aldo, as well as for the higher efficacy and potency of finerenone at blocking Aldo-induced apoptosis, oxidative stress, and fibrosis. CONCLUSION Finerenone, but not eplerenone, induces GRK5-dependent cardiac MR inhibition, which underlies, at least in part, its higher potency and efficacy, compared to eplerenone, as an MRA in the heart. GRK5 acts as a co-repressor of the cardiac MR and is essential for efficient MR antagonism in the myocardium

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“…In fact, adrenal β-arrestin1 is absolutely essential for disease-associated hyperaldosteronism, since its absence results in normal circulating aldosterone levels even in the presence of MI [ 102 ]. Importantly, catecholamine-activated βARs were recently shown to enhance AT 1 R-dependent aldosterone production via GRK2-mediated receptor crosstalk in adrenocortical cells [ 177 ]. Thus, it appears that the catecholamine and aldosterone secretion pathways are intricately interposed in the adrenal gland via β-arrestin-dependent signaling [ 178 , 179 ].…”

Section: Aldosterone-induced Adrenergic Receptor Dysfunction In the Failing Myocardiummentioning

confidence: 99%

Impact of Aldosterone on the Failing Myocardium: Insights from Mitochondria and Adrenergic Receptors Signaling and Function

Guitart‐Mampel

Urquiza

Borges

et al. 2021

Cells

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The mineralocorticoid aldosterone regulates electrolyte and blood volume homeostasis, but it also adversely modulates the structure and function of the chronically failing heart, through its elevated production in chronic human post-myocardial infarction (MI) heart failure (HF). By activating the mineralocorticoid receptor (MR), a ligand-regulated transcription factor, aldosterone promotes inflammation and fibrosis of the heart, while increasing oxidative stress, ultimately induding mitochondrial dysfunction in the failing myocardium. To reduce morbidity and mortality in advanced stage HF, MR antagonist drugs, such as spironolactone and eplerenone, are used. In addition to the MR, aldosterone can bind and stimulate other receptors, such as the plasma membrane-residing G protein-coupled estrogen receptor (GPER), further complicating it signaling properties in the myocardium. Given the salient role that adrenergic receptor (ARs)—particularly βARs—play in cardiac physiology and pathology, unsurprisingly, that part of the impact of aldosterone on the failing heart is mediated by its effects on the signaling and function of these receptors. Aldosterone can significantly precipitate the well-documented derangement of cardiac AR signaling and impairment of AR function, critically underlying chronic human HF. One of the main consequences of HF in mammalian models at the cellular level is the presence of mitochondrial dysfunction. As such, preventing mitochondrial dysfunction could be a valid pharmacological target in this condition. This review summarizes the current experimental evidence for this aldosterone/AR crosstalk in both the healthy and failing heart, and the impact of mitochondrial dysfunction in HF. Recent findings from signaling studies focusing on MR and AR crosstalk via non-conventional signaling of molecules that normally terminate the signaling of ARs in the heart, i.e., the G protein-coupled receptor-kinases (GRKs), are also highlighted.

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GRK2-Mediated Crosstalk Between β-Adrenergic and Angiotensin II Receptors Enhances Adrenocortical Aldosterone Production In Vitro and In Vivo

Cited by 12 publications

References 36 publications

G Protein-Coupled Receptor Kinase 2 as Novel Therapeutic Target in Fibrotic Diseases

G Protein-Coupled Receptor Kinase 2 as Novel Therapeutic Target in Fibrotic Diseases

GRK5 is an essential co-repressor of the cardiac mineralocorticoid receptor and is selectively induced by finerenone

Impact of Aldosterone on the Failing Myocardium: Insights from Mitochondria and Adrenergic Receptors Signaling and Function

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