Endothelins in cardiovascular biology and therapeutics

Dhaun, Neeraj; Webb, David J.

doi:10.1038/s41569-019-0176-3

Cited by 164 publications

(133 citation statements)

References 107 publications

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“…The difference in ETA protein synthesis between the 5/6 nephrectomy and adenine models may also have resulted from the different characteristics between the models; i.e., the presence of proteinuria and elevated BP in the 5/6 nephrectomy model. Both proteinuria and renal damage have been linked in a vicious-circle-like manner to pathological ET-system activation, while treatment with ETA antagonists has been shown to have antiproteinuric effects [12].…”

Section: Discussionmentioning

confidence: 99%

“…Three weeks after sham or 5/6 nephrectomy operation (NX), rats received either the control diet or the 2.0% oxonic acid diet for 9 weeks. The groups and the animal numbers were Sham (n=12), Sham+Oxo (n=12), NX (12) and NX+Oxo (n=12). We previously published the study protocol in more detail, and essential demographic and laboratory results of the study groups were included in the previous reports [30][31][32].…”

Section: Twelve-weeks Of Chronic Renal Insufficiency Induced By 5/6 Nmentioning

confidence: 99%

“…Under physiological conditions, 70% of the ET-receptors in both the cortex and medulla of the human kidney are ETB, whereas ETA is the predominant form in the smooth muscle of the renal vasculature [11].In addition to ET-1 upregulation, CKD is associated with putative changes in the ETB versus ETA balance [2]. Elevated ET-1 concentration in CKD may result from both increased production and decreased elimination, as reduced ETB scavenger receptor activity might explain the increased ET-1 concentration in CKD [12]. Furthermore, ETB receptor activation increases endothelial nitric oxide (NO) release, which counteracts the vasoconstrictive effects of ET-1 and also down-regulates ET-1 production [13].…”

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confidence: 99%

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Unfavorable Reduction in the Ratio of Endothelin B to A Receptors in Experimental 5/6 Nephrectomy and Adenine Models of Chronic Renal Insufficiency

Törmänen

Lakkisto

Eräranta

et al. 2020

IJMS

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Chronic renal insufficiency (CRI) is characterized by increased endothelin 1 (ET-1) synthesis. We studied rat kidney endothelin receptor A (ETA) and receptor B (ETB) expressions after 12 and 27 weeks of 5/6 nephrectomy, and after 12 weeks of 0.3% adenine diet, representing proteinuric and interstitial inflammation models of CRI, respectively. Uric acid and calcium-phosphate metabolism were modulated after 5/6 nephrectomy, while ETA blocker and calcimimetic were given with adenine. Endothelin receptor mRNA levels were measured using RT-qPCR and protein levels using autoradiography (5/6 nephrectomy) or ELISA (adenine model). Both 12 and 27 weeks after 5/6 nephrectomy, kidney cortex ETA protein was increased by ~60% without changes in ETB protein, and the ETB:ETA ratio was reduced. However, the ETB:ETA mRNA ratio did not change. In the adenine model, kidney ETA protein was reduced by ~70%, while ETB protein was suppressed by ~95%, and the ETB:ETA ratio was reduced by ~85%, both at the protein and mRNA levels. The additional interventions did not influence the observed reductions in the ETB:ETA ratio. To conclude, unfavorable reduction in the ETB:ETA protein ratio was observed in two different models of CRI. Therefore, ETA blockade may be beneficial in a range of diseases that cause impaired kidney function.

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Section: Discussionmentioning

confidence: 99%

Section: Twelve-weeks Of Chronic Renal Insufficiency Induced By 5/6 Nmentioning

confidence: 99%

mentioning

confidence: 99%

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Unfavorable Reduction in the Ratio of Endothelin B to A Receptors in Experimental 5/6 Nephrectomy and Adenine Models of Chronic Renal Insufficiency

Törmänen

Lakkisto

Eräranta

et al. 2020

IJMS

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“…ET-1 signaling works through two receptors, ETAR and ETBR, via paracrine and autocrine action (Dhaun and Webb, 2019). ETAR and ETBR exert largely opposite effects, and ET-1 stimulation of ETAR is primarily responsible for renal injury.…”

Section: Introductionmentioning

confidence: 99%

EDN1-AS, A Novel Long Non-coding RNA Regulating Endothelin-1 in Human Proximal Tubule Cells

et al. 2020

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Endothelin-1 (ET-1) is a peptide hormone that functions as a vasoconstrictor in the vasculature, whereas in the collecting duct of the kidney it exerts blood pressurelowering effects via natriuretic actions. Aberrant ET-1 signaling is associated with several pathological states including hypertension and chronic kidney disease. ET-1 expression is regulated largely through transcriptional control of the gene that encodes ET-1, EDN1. Here we report a long, non-coding RNA (lncRNA) that appears to be antisense to the EDN1 gene, called EDN1-AS. Because EDN1-AS represents a potential novel mechanism to regulate ET-1 expression, we examined the regulation of EDN1-AS expression and action. A putative glucocorticoid receptor response (GR) element upstream of the predicted EDN1-AS transcription start site was identified using the ENCODE database and the UCSC genome browser. Two homozygous deletion clones of the element were generated using CRISPR/Cas9. This deletion resulted in a significant increase in the expression of EDN1-AS, which was associated with increased secretion of ET-1 peptide from HK-2 cells (two-fold increase in KO cells vs. CNTL, n = 7, P < 0.05). Phenotypic characterization of these CRISPR clones revealed a difference in cell growth rates. Using a standard growth assay, we determined that the KO1 clone exhibited a three-fold increase in growth over 8 days compared to control cells (n = 4, P < 0.01) and the KO2 clone exhibited a two-fold increase (n = 4, P < 0.01). These results support a role for EDN1-AS as a novel regulatory mechanism of ET-1 expression and cellular proliferation.

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“…Endothelin-1 (ET-1) is a major vasoconstrictor derived from endothelial cells [6]. Today, endothelin receptor agonist is widely used for PAH treatment, and has contributed to the improvement of PAH prognosis.…”

Section: Introductionmentioning

confidence: 99%

Endothelin-1 upregulates activin receptor-like kinase-1 expression via Gi/RhoA/Sp-1/Rho kinase pathways at transcriptional and post-transcriptional levels in human pulmonary arterial endothelial cells

Sugimoto

Yokokawa

Misaka

et al. 2020

Preprint

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BackgroundsPulmonary arterial hypertension (PAH) is a disease with poor prognosis that is characterized by pulmonary vasoconstriction and organic stenosis due to abnormal proliferation of pulmonary vascular cells. It has been demonstrated that endothelin (ET)-1 induces pulmonary vasoconstriction through activation of RhoA. Moreover, we previously demonstrated that Gi, a heterotrimeric G protein, functions upstream of RhoA activation. A gene mutation of activin receptor-like kinase (ACVRL)-1 is recognized in idiopathic or heritable PAH patients. However, little is known about the association between ET-1 and ACVRL-1. In the present study, we investigated the effect of ET-1 on ACVRL-1 expression and aimed to delineate the involvement of the Gi/RhoA/Rho kinase pathway.MethodsET-1 was added to culture medium of human pulmonary arterial endothelial cells (PAECs), and ACVRL-1 expression levels were analyzed using western blotting and quantitative polymerase chain reaction. The promoter activity of ACVRL-1 was evaluated by dual luciferase assay. Before adding ET-1 to the PAECs, pretreatment with pertussis toxin (PTX) or exoenzyme C3 transferase (C3T) was performed for the inhibition of Gi or RhoA, respectively. Rho kinase was inhibited by Y27632. Active form of RhoA (GTP-RhoA) was assessed by pull-down assay.ResultsACVRL-1 expression was increased by ET-1 in the PAECs. Pull-down assay revealed that ET-1 rapidly induced a GTP-loading of RhoA. The ET-1-induced RhoA activation was suppressed by pretreatment with PTX or C3T. Further, PTX, C3T, and Y27632 suppressed the ET-1-induced ACVRL-1 expression. The activity of ACVRL-1 promotor and the lifespan of ACVRL-1 mRNA was increased by ET-1. Sp-1, which is one of the transcriptional factors of ACVRL-1, peaked 15 min after adding ET-1 to the PAECs. PTX and C3T prevented the increase of Sp-1 induced by ET-1.ConclusionThe present study demonstrated that ET-1 increases ACVRL-1 expression at the transcriptional and post-transcriptional levels in human PAECs via the Gi/RhoA/Rho kinase pathway with involvement of Sp-1.

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Endothelins in cardiovascular biology and therapeutics

Cited by 164 publications

References 107 publications

Unfavorable Reduction in the Ratio of Endothelin B to A Receptors in Experimental 5/6 Nephrectomy and Adenine Models of Chronic Renal Insufficiency

Unfavorable Reduction in the Ratio of Endothelin B to A Receptors in Experimental 5/6 Nephrectomy and Adenine Models of Chronic Renal Insufficiency

EDN1-AS, A Novel Long Non-coding RNA Regulating Endothelin-1 in Human Proximal Tubule Cells

Endothelin-1 upregulates activin receptor-like kinase-1 expression via Gi/RhoA/Sp-1/Rho kinase pathways at transcriptional and post-transcriptional levels in human pulmonary arterial endothelial cells

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