Endothelin in Nondiabetic Chronic Kidney Disease: Preclinical and Clinical Studies

Culshaw, Geoff; MacIntyre, I.; Dhaun, Neeraj; Webb, David J.

doi:10.1016/j.semnephrol.2015.03.002

Cited by 13 publications

(8 citation statements)

References 118 publications

(115 reference statements)

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“…It is suggested that there is a synergistic relationship between Ang II and ET-1 and Ang II upregulates vascular and renal ET-1 expression and release [40]. Furthermore, ET-1 contributes to renal inflammation by promoting migration of monocytes and macrophages by increasing the expression of MCP-1, and ET-1 also contributes to renal fibrosis by stimulating the synthesis of ECM [41].…”

Section: Discussionmentioning

confidence: 99%

Liraglutide Improves the Kidney Function in a Murine Model of Chronic Kidney Disease

Ougaard

Sembach

Jensen

et al. 2020

Nephron

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Background: Chronic kidney disease (CKD) is a global health burden, and the current treatment options only slow down the disease progression. GLP-1 receptor agonists (GLP-1 RA) have shown a renal protective effect in models of CKD; however, the mechanism behind the beneficial effect is not understood. In this study, we investigate the effect of the GLP-1 RA liraglutide in the nephrotoxic serum nephritis (NTN) CKD model. Moreover, we compare the gene expression pattern of liraglutide-treated mice to the gene expression pattern of mice treated with the angiotensin converting enzyme inhibitor, enalapril. Methods: The effect of liraglutide was tested in the NTN model by evaluating the glomerular filtration rate (GFR), albuminuria, mesangial expansion, renal fibrosis, and renal inflammation. Furthermore, the regulation of selected genes involved in CKD and in glomerular, cortical tubulointerstitial, and whole kidney structures was analyzed using a gene expression array on samples following laser capture microdissection. Results: Treatment with liraglutide improved CKD hallmarks including GFR, albuminuria, mesangial expansion, renal inflammation, and renal fibrosis. The gene expression revealed that both liraglutide and enalapril reversed the regulation of several fibrosis and inflammation associated genes, which are also regulated in human CKD patients. Furthermore, liraglutide and enalapril both regulated genes in the kidney involved in blood pressure control. Conclusions: Treatment with liraglutide improved the kidney function and diminished renal lesions in NTN-induced mice. Both liraglutide and enalapril reversed the regulation of genes involved in CKD and regulated genes involved in blood pressure control.

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Section: Discussionmentioning

confidence: 99%

Liraglutide Improves the Kidney Function in a Murine Model of Chronic Kidney Disease

Ougaard

Sembach

Jensen

et al. 2020

Nephron

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“…The rapid clearance of ET‐1 by the pulmonary, splanchnic and renal circulations, associated with its local processing, implies that ET‐1 is an autocrine or paracrine mediator rather than a systemic hormone (Culshaw et al . ).…”

Section: Endothelium‐dependent Contractionsmentioning

confidence: 97%

Endothelial dysfunction and vascular disease - a 30th anniversary update

Vanhoutte¹,

et al. 2016

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The endothelium can evoke relaxations of the underlying vascular smooth muscle, by releasing vasodilator substances. The best-characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO) which activates soluble guanylyl cyclase in the vascular smooth muscle cells, with the production of cyclic guanosine monophosphate (cGMP) initiating relaxation. The endothelial cells also evoke hyperpolarization of the cell membrane of vascular smooth muscle (endothelium-dependent hyperpolarizations, EDH-mediated responses). As regards the latter, hydrogen peroxide (H O ) now appears to play a dominant role. Endothelium-dependent relaxations involve both pertussis toxin-sensitive G (e.g. responses to α -adrenergic agonists, serotonin, and thrombin) and pertussis toxin-insensitive G (e.g. adenosine diphosphate and bradykinin) coupling proteins. New stimulators (e.g. insulin, adiponectin) of the release of EDRFs have emerged. In recent years, evidence has also accumulated, confirming that the release of NO by the endothelial cell can chronically be upregulated (e.g. by oestrogens, exercise and dietary factors) and downregulated (e.g. oxidative stress, smoking, pollution and oxidized low-density lipoproteins) and that it is reduced with ageing and in the course of vascular disease (e.g. diabetes and hypertension). Arteries covered with regenerated endothelium (e.g. following angioplasty) selectively lose the pertussis toxin-sensitive pathway for NO release which favours vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. In addition to the release of NO (and EDH, in particular those due to H O ), endothelial cells also can evoke contraction of the underlying vascular smooth muscle cells by releasing endothelium-derived contracting factors. Recent evidence confirms that most endothelium-dependent acute increases in contractile force are due to the formation of vasoconstrictor prostanoids (endoperoxides and prostacyclin) which activate TP receptors of the vascular smooth muscle cells and that prostacyclin plays a key role in such responses. Endothelium-dependent contractions are exacerbated when the production of nitric oxide is impaired (e.g. by oxidative stress, ageing, spontaneous hypertension and diabetes). They contribute to the blunting of endothelium-dependent vasodilatations in aged subjects and essential hypertensive and diabetic patients. In addition, recent data confirm that the release of endothelin-1 can contribute to endothelial dysfunction and that the peptide appears to be an important contributor to vascular dysfunction. Finally, it has become clear that nitric oxide itself, under certain conditions (e.g. hypoxia), can cause biased activation of soluble guanylyl cyclase leading to the production of cyclic inosine monophosphate (cIMP) rather than cGMP and hence causes contraction rather than relaxation of the underlying vascular smooth muscle.

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“…To date nearly 28,000 endothelin-related papers and reviews have been published. The following should be consulted for more detailed information on ET pharmacology, physiology, and pathology: antagonists ( Kohan et al, 2012 ; Clozel et al, 2013 ; Maguire and Davenport, 2015 ), the heart ( Drawnel et al, 2013 ; Chester and Yacoub, 2014 ; Nasser and El-Mas 2014 ), kidney ( Kohan et al, 2011a , b ; Hyndman and Pollock, 2013 ; Boesen, 2015 ; Culshaw et al, 2015 ), vasculature ( Sandoval et al, 2014 ), hypertension ( Schiffrin, 2001 ; Rautureau and Schiffrin, 2012 ; Speed and Pollock, 2013 ; Laffin and Bakris, 2015 ), atherosclerosis and diabetes ( Pernow et al, 2012 ), cancer ( Rosanò et al, 2013a ; Irani et al, 2014 ), and PAH ( Moorhouse et al, 2013 ; Miyagawa and Emoto 2014 ). The International Union of Pharmacology/British Pharmacological Society (IUPHAR/BPS) curated database, Guide to PHARMACOLOGY, provides detailed information on pharmacological parameters for ET ligands ( Davenport et al, 2015 ).…”

Section: Historical Introductionmentioning

confidence: 99%

Endothelin

et al. 2016

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The endothelins comprise three structurally similar 21-amino acid peptides. Endothelin-1 and -2 activate two G-protein coupled receptors, ETA and ETB, with equal affinity, whereas endothelin-3 has a lower affinity for the ETA subtype. Genes encoding the peptides are present only among vertebrates. The ligand-receptor signaling pathway is a vertebrate innovation and may reflect the evolution of endothelin-1 as the most potent vasoconstrictor in the human cardiovascular system with remarkably long lasting action. Highly selective peptide ETA and ETB antagonists and ETB agonists together with radiolabeled analogs have accurately delineated endothelin pharmacology in humans and animal models, although surprisingly no ETA agonist has been discovered. ET antagonists (bosentan, ambrisentan) have revolutionized the treatment of pulmonary arterial hypertension, with the next generation of antagonists exhibiting improved efficacy (macitentan). Clinical trials continue to explore new applications, particularly in renal failure and for reducing proteinuria in diabetic nephropathy. Translational studies suggest a potential benefit of ETB agonists in chemotherapy and neuroprotection. However, demonstrating clinical efficacy of combined inhibitors of the endothelin converting enzyme and neutral endopeptidase has proved elusive. Over 28 genetic modifications have been made to the ET system in mice through global or cell-specific knockouts, knock ins, or alterations in gene expression of endothelin ligands or their target receptors. These studies have identified key roles for the endothelin isoforms and new therapeutic targets in development, fluid-electrolyte homeostasis, and cardiovascular and neuronal function. For the future, novel pharmacological strategies are emerging via small molecule epigenetic modulators, biologicals such as ETB monoclonal antibodies and the potential of signaling pathway biased agonists and antagonists.

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Endothelin in Nondiabetic Chronic Kidney Disease: Preclinical and Clinical Studies

Cited by 13 publications

References 118 publications

Liraglutide Improves the Kidney Function in a Murine Model of Chronic Kidney Disease

Liraglutide Improves the Kidney Function in a Murine Model of Chronic Kidney Disease

Endothelial dysfunction and vascular disease - a 30th anniversary update

Endothelin

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