scholarly journals Regulator of G protein signaling 2 is a functionally important negative regulator of angiotensin II-induced cardiac fibroblast responses

2011 ◽  
Vol 301 (1) ◽  
pp. H147-H156 ◽  
Author(s):  
Peng Zhang ◽  
Jialin Su ◽  
Michelle E. King ◽  
Angel E. Maldonado ◽  
Cindy Park ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Angiotensin Ii ◽  
G Protein ◽  
Cardiac Fibroblasts ◽  
Negative Regulator ◽  
G Protein Signaling ◽  
Ang Ii ◽  
Protein Signaling ◽  
Important Negative Regulator

Cardiac fibroblasts play a key role in fibrosis development in response to stress and injury. Angiotensin II (ANG II) is a major profibrotic activator whose downstream effects (such as phospholipase Cβ activation, cell proliferation, and extracellular matrix secretion) are mainly mediated via Gq-coupled AT1 receptors. Regulators of G protein signaling (RGS), which accelerate termination of G protein signaling, are expressed in the myocardium. Among them, RGS2 has emerged as an important player in modulating Gq-mediated hypertrophic remodeling in cardiac myocytes. To date, no information is available on RGS in cardiac fibroblasts. We tested the hypothesis that RGS2 is an important regulator of ANG II-induced signaling and function in ventricular fibroblasts. Using an in vitro model of fibroblast activation, we have demonstrated expression of several RGS isoforms, among which only RGS2 was transiently upregulated after short-term ANG II stimulation. Similar results were obtained in fibroblasts isolated from rat hearts after in vivo ANG II infusion via minipumps for 1 day. In contrast, prolonged ANG II stimulation (3–14 days) markedly downregulated RGS2 in vivo. To delineate the functional effects of RGS expression changes, we used gain- and loss-of-function approaches. Adenovirally infected RGS2 had a negative regulatory effect on ANG II-induced phospholipase Cβ activity, cell proliferation, and total collagen production, whereas RNA interference of endogenous RGS2 had opposite effects, despite the presence of several other RGS. Together, these data suggest that RGS2 is a functionally important negative regulator of ANG II-induced cardiac fibroblast responses that may play a role in ANG II-induced fibrosis development.

scholarly journals Regulators of G-protein signaling 4 in adrenal gland: localization, regulation, and role in aldosterone secretion

2007 ◽  
Vol 194 (2) ◽  
pp. 429-440 ◽  
Author(s):  
Damian G Romero ◽  
Ming Yi Zhou ◽  
Licy L Yanes ◽  
Maria W Plonczynski ◽  
Tanganika R Washington ◽  
...  
Keyword(s):  
Adrenal Gland ◽  
G Protein ◽  
Intracellular Signaling ◽  
Zona Glomerulosa ◽  
G Protein Signaling ◽  
Ang Ii ◽  
Protein Signaling ◽  
Aldosterone Secretion ◽  
H295r Cells

Regulators of G-protein signaling (RGS proteins) interact with Gα subunits of heterotrimeric G-proteins, accelerating the rate of GTP hydrolysis and finalizing the intracellular signaling triggered by the G-protein-coupled receptor (GPCR)–ligand interaction. Angiotensin II (Ang II) interacts with its GPCR in adrenal zona glomerulosa cells and triggers a cascade of intracellular signals that regulates steroidogenesis and proliferation. On screening for adrenal zona glomerulosa-specific genes, we found that RGS4 was exclusively localized in the zona glomerulosa of the rat adrenal cortex. We studied RGS4 expression and regulation in the rat adrenal gland, including the signaling pathways involved, as well as the role of RGS4 in steroidogenesis in human adrenocortical H295R cells. We reported that RGS4 mRNA expression in the rat adrenal gland was restricted to the adrenal zonal glomerulosa and upregulated by low-salt diet and Ang II infusion in rat adrenal glands in vivo. In H295R cells, Ang II caused a rapid and transient increase in RGS4 mRNA levels mediated by the calcium/calmodulin/calmodulin-dependent protein kinase and protein kinase C pathways. RGS4 overexpression by retroviral infection in H295R cells decreased Ang II-stimulated aldosterone secretion. In reporter assays, RGS4 decreased Ang II-mediated aldosterone synthase upregulation. In summary, RGS4 is an adrenal gland zona glomerulosa-specific gene that is upregulated by aldosterone secretagogues, in vivo and in vitro, and functions as a negative feedback of Ang II-triggered intracellular signaling. Alterations in RGS4 expression levels or functions may be involved in deregulations of Ang II signaling and abnormal aldosterone secretion.

scholarly journals Regulator of G protein signaling 17 represents a novel target for treating cisplatin induced hearing loss

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Asmita Dhukhwa ◽  
Raheem F. H. Al Aameri ◽  
Sandeep Sheth ◽  
Debashree Mukherjea ◽  
Leonard Rybak ◽  
...  
Keyword(s):  
Hearing Loss ◽  
G Protein ◽  
Protein Interactions ◽  
Cannabinoid Receptor ◽  
Significant Proportion ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Drug Induced ◽  
Male Wistar Rats

AbstractRegulators of G protein signaling (RGS) accelerate the GTPase activity of G proteins to enable rapid termination of the signals triggered by G protein-coupled receptors (GPCRs). Activation of several GPCRs, including cannabinoid receptor 2 (CB2R) and adenosine A1 receptor (A1AR), protects against noise and drug-induced ototoxicity. One such drug, cisplatin, an anticancer agent used to treat various solid tumors, produces permanent hearing loss in experimental animals and in a high percentage of cancer patients who undergo treatments. In this study we show that cisplatin induces the expression of the RGS17 gene and increases the levels of RGS17 protein which contributes to a significant proportion of the hearing loss. Knockdown of RGS17 suppressed cisplatin-induced hearing loss in male Wistar rats, while overexpression of RGS17 alone produced hearing loss in vivo. Furthermore, RGS17 and CB2R negatively regulate the expression of each other. These data suggest that RGS17 mediates cisplatin ototoxicity by uncoupling cytoprotective GPCRs from their normal G protein interactions, thereby mitigating the otoprotective contributions of endogenous ligands of these receptors. Thus, RGS17 represents a novel mediator of cisplatin ototoxicity and a potential therapeutic target for treating hearing loss.

scholarly journals Patients with Mutations in Gsα Have Reduced Activation of a Downstream Target in Epithelial Tissues due to Haploinsufficiency

2007 ◽  
Vol 92 (10) ◽  
pp. 3941-3948
Author(s):  
Stephanie C. Hsu ◽  
Joshua D. Groman ◽  
Christian A. Merlo ◽  
Kathleen Naughton ◽  
Pamela L. Zeitlin ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
G Protein ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Downstream Target ◽  
Epithelial Tissues ◽  
Stimulatory G Protein ◽  
Normal Controls

Abstract Context: Patients with Albright hereditary osteodystrophy (AHO) have defects in stimulatory G protein signaling due to loss of function mutations in GNAS. The mechanism by which these mutations lead to the AHO phenotype has been difficult to establish due to the inaccessibility of the affected tissues. Objective: The objective of the study was to gain insight into the downstream consequences of abnormal stimulatory G protein signaling in human epithelial tissues. Patients and Design: We assessed transcription of GNAS and Gsα-stimulated activation of the cystic fibrosis transmembrane conductance regulator (CFTR) in AHO patients, compared with normal controls and patients with cystic fibrosis. Main Outcome Measures: Relative expression of Gsα transcripts from each parental GNAS allele and cAMP measurements from nasal epithelial cells were compared among normal controls and AHO patients. In vivo measurements of CFTR function, pulmonary function, and pancreatic function were assessed in AHO patients. Results: GNAS was expressed equally from each allele in normals and two of five AHO patients. cAMP generation was significantly reduced in nasal respiratory epithelial cells from AHO patients, compared with normal controls (0.4 vs. 0.6, P = 0.0008). Activation of CFTR in vivo in nasal (P = 0.0065) and sweat gland epithelia (P = 0.01) of AHO patients was significantly reduced from normal. In three patients, the reduction in activity was comparable with patients with cystic fibrosis due to mutations in CFTR. Yet no AHO patients had pulmonary or pancreatic disease consistent with cystic fibrosis. Conclusions: In humans, haploinsufficiency of GNAS causes a significant reduction in the activation of the downstream target, CFTR, in vivo.

Tanshinone IIA Inhibits Angiotensin II-Induced Cell Proliferation in Rat Cardiac Fibroblasts

2011 ◽  
Vol 39 (02) ◽  
pp. 381-394 ◽  
Author(s):  
Paul Chan ◽  
Ju-Chi Liu ◽  
Li-Jen Lin ◽  
Po-Yuan Chen ◽  
Tzu-Hurng Cheng ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cell Proliferation ◽  
Angiotensin Ii ◽  
Cardiac Fibroblasts ◽  
Tanshinone Iia ◽  
No Production ◽  
Ang Ii ◽  
Erk Phosphorylation ◽  
Enos Phosphorylation ◽  
Ros Formation

Tanshinone IIA extracted from Danshen, a popular medicinal herb used in traditional Chinese medicine, exhibits cardio-protective effects. However, the mechanism of its cardioprotective effect is not well established. The aims of this study were to examine whether tanshinone IIA may alter angiotensin II (Ang II)-induced cell proliferation and to identify the putative underlying signaling pathways in rat cardiac fibroblasts. Cultured rat cardiac fibroblasts were pre-treated with tanshinone IIA and stimulated with Ang II, cell proliferation and endothelin-1 (ET-1) expression were examined. The effect of tanshinone IIA on Ang II-induced reactive oxygen species (ROS) formation, and extracellular signal-regulated kinase (ERK) phosphorylation were also examined. In addition, the effect of tanshinone IIA on nitric oxide (NO) production, and endothelial nitric oxide synthase (eNOS) phosphorylation were tested to elucidate the intracellular mechanism. The increased cell proliferation and ET-1 expression by Ang II (100 nM) were partially inhibited by tanshinone IIA. Tanshinone IIA also inhibited Ang II-increased ROS formation, and ERK phosphorylation. In addition, tanshinone IIA was found to increase the NO generation, and eNOS phosphorylation. NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOS, and the short interfering RNA transfection for eNOS markedly attenuated the inhibitory effect of tanshinone IIA on Ang II-induced cell proliferation. The results suggest that tanshinone IIA prevents cardiac fibroblast proliferation by interfering with the generation of ROS and involves the activation of the eNOS-NO pathway.

scholarly journals Endogenous modification of the chemoattractant CXCL5 alters receptor usage and enhances its activity toward neutrophils and monocytes

2021 ◽  
Vol 14 (673) ◽  
pp. eaax3053
Author(s):  
Mieke Metzemaekers ◽  
Anneleen Mortier ◽  
Alessandro Vacchini ◽  
Daiane Boff ◽  
Karen Yu ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
G Protein ◽  
Chemotactic Activity ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Agonist Activity ◽  
N Terminus ◽  
G Protein Coupled

The inflammatory human chemokine CXCL5 interacts with the G protein–coupled receptor CXCR2 to induce chemotaxis and activation of neutrophils. CXCL5 also has weak agonist activity toward CXCR1. The N-terminus of CXCL5 can be modified by proteolytic cleavage or deimination of Arg9 to citrulline (Cit), and these modifications can occur separately or together. Here, we chemically synthesized native CXCL5(1–78), truncated CXCL5 [CXCL5(9–78)], and the citrullinated (Cit9) versions and characterized their functions in vitro and in vivo. Compared with full-length CXCL5, N-terminal truncation resulted in enhanced potency to induce G protein signaling and β-arrestin recruitment through CXCR2, increased CXCL5-initiated internalization of CXCR2, and greater Ca2+ signaling downstream of not only CXCR2 but also CXCR1. Citrullination did not affect the capacity of CXCL5 to activate classical or alternative signaling pathways. Administering the various CXCL5 forms to mice revealed that in addition to neutrophils, CXCL5 exerted chemotactic activity toward monocytes and that this activity was increased by N-terminal truncation. These findings were confirmed by in vitro chemotaxis and Ca2+ signaling assays with primary human CD14+ monocytes and human THP-1 monocytes. In vitro and in vivo analyses suggested that CXCL5 targeted monocytes through CXCR1 and CXCR2. Thus, truncation of the N-terminus makes CXCL5 a more potent chemoattractant for both neutrophils and monocytes that acts through CXCR1 and CXCR2.

scholarly journals The regulator of G-protein signaling RGS16 promotes insulin secretion and β-cell proliferation in rodent and human islets

2016 ◽  
Vol 5 (10) ◽  
pp. 988-996 ◽  
Author(s):  
Kevin Vivot ◽  
Valentine S. Moullé ◽  
Bader Zarrouki ◽  
Caroline Tremblay ◽  
Arturo D. Mancini ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
G Protein ◽  
Human Islets ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Β Cell

Control of adrenal cell proliferation by AT1 receptors in response to angiotensin II and low-sodium diet

1999 ◽  
Vol 276 (2) ◽  
pp. E303-E309 ◽  
Author(s):  
Pauline E. McEwan ◽  
Gavin P. Vinson ◽  
Christopher J. Kenyon
Keyword(s):  
Cell Proliferation ◽  
Angiotensin Ii ◽  
Zona Glomerulosa ◽  
Ang Ii ◽  
Adrenal Cell ◽  
Sodium Diet ◽  
Low Sodium Diet ◽  
Low Sodium ◽  
Glomerulosa Cells

The effects of angiotensin II (ANG II), the angiotensin type 1 (AT1) receptor antagonist losartan, and low-sodium diet on rat adrenal cell proliferation were studied in vivo with immunocytochemistry. Both ANG II and low-sodium diet increased proliferation of endothelial cells of the zona glomerulosa. Losartan prevented ANG II-induced hyperplasia of glomerulosa cells but not the effects of a low-sodium diet. Glomerulosa cells after ANG II + losartan treatment appeared hypertrophied compared with those of controls. Proliferative effects of ANG II and low-sodium diet in the reticularis were blocked by losartan. No changes were seen in the fasciculata. Proliferation in the medulla was increased with losartan, was decreased by ANG II, but was unaffected by low-sodium diet. In conclusion, 1) cell hypertrophy and proliferation of glomerulosa cells are mediated by AT1 receptor-dependent and -independent processes, 2) proliferation of reticularis cells is controlled by AT1 receptors, and 3) reciprocal control of chromaffin cell proliferation by ANG II may involve indirect AT1-dependent processes.

scholarly journals Proximal tubule NHE3 activity is inhibited by beta-arrestin-biased angiotensin II type 1 receptor signaling

2015 ◽  
Vol 309 (8) ◽  
pp. C541-C550 ◽  
Author(s):  
Carla P. Carneiro de Morais ◽  
Juliano Z. Polidoro ◽  
Donna L. Ralph ◽  
Thaissa D. Pessoa ◽  
Maria Oliveira-Souza ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
G Protein ◽  
Extracellular Fluid ◽  
The Body ◽  
Type I ◽  
Ang Ii ◽  
Receptor Signaling

Physiological concentrations of angiotensin II (ANG II) upregulate the activity of Na+/H+ exchanger isoform 3 (NHE3) in the renal proximal tubule through activation of the ANG II type I (AT1) receptor/G protein-coupled signaling. This effect is key for maintenance of extracellular fluid volume homeostasis and blood pressure. Recent findings have shown that selective activation of the beta-arrestin-biased AT1 receptor signaling pathway induces diuresis and natriuresis independent of G protein-mediated signaling. This study tested the hypothesis that activation of this AT1 receptor/beta-arrestin signaling inhibits NHE3 activity in proximal tubule. To this end, we determined the effects of the compound TRV120023, which binds to the AT1R, blocks G-protein coupling, and stimulates beta-arrestin signaling on NHE3 function in vivo and in vitro. NHE3 activity was measured in both native proximal tubules, by stationary microperfusion, and in opossum proximal tubule (OKP) cells, by Na+-dependent intracellular pH recovery. We found that 10−7 M TRV120023 remarkably inhibited proximal tubule NHE3 activity both in vivo and in vitro. Additionally, stimulation of NHE3 by ANG II was completely suppressed by TRV120023 both in vivo as well as in vitro. Inhibition of NHE3 activity by TRV120023 was associated with a decrease in NHE3 surface expression in OKP cells and with a redistribution from the body to the base of the microvilli in the rat proximal tubule. These findings indicate that biased signaling of the beta-arrestin pathway through the AT1 receptor inhibits NHE3 activity in the proximal tubule at least in part due to changes in NHE3 subcellular localization.

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