The endothelin receptor antagonist ameliorates the hypertensive phenotypes of transgenic hypertensive mice with renin-angiotensin genes and discloses roles of organ specific activation of endothelin system in transgenic mice

Maki, Sunao; Miyauchi, Takashi; Kakinuma, Yoshihiko; Sakai, Satoshi; Kobayashi, Tsutomu; Sugiyama, Fumihiro; Fukamizu, Akiyoshi; Goto, Katsutoshi; Yamaguchi, Iwao

doi:10.1016/j.lfs.2003.07.034

Cited by 9 publications

(4 citation statements)

References 43 publications

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“…In contrast to the nonselective ERA, selective ET A blockade substantially reduced blood pressure, ameliorated glomerulosclerosis and strongly improved survival [84]. The more favourable effects of ET A blockade were evident irrespective of high-or low-salt diet [86]. It is increasingly recognized that elevated salt sensitivity in aged individuals contributes to the age-related increase in blood pressure, end organ damage and cardiovascular events, and that the renal ET system is implicated in this process.…”

Section: Results From Animal Studiesmentioning

confidence: 98%

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Endothelin receptor selectivity in chronic kidney disease: rationale and review of recent evidence

Neuhofer¹,

Pittrow

2009

Eur J Clin Investigation

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Endothelin (ET) is a potent vasoconstrictory peptide with proinflammatory and profibrotic properties that exerts its biological effects through two pharmacologically distinct receptor subtypes, namely ET(A) and ET(B). In addition to its substantial contribution to normal renal function, a large body of evidence suggests that derangement of the renal ET system is involved in the initiation and progression of chronic kidney disease (CKD) in diabetes, hypertension and glomerulonephritis. Thus, the use of ET receptor antagonists (ERAs) may offer potential novel treatment strategies in CKD. Recent literature on the role of the renal ET system in the healthy kidney was reviewed. In addition, an unbiased PubMed search was performed for studies published during the last 5 years that addressed the effects of ERAs in CKD. A particular objective was to extract information regarding whether selective or nonselective ERAs may have therapeutic potential in humans. ET-1 acts primarily as an autocrine or paracrine factor in the kidney. In normal physiology, ET-1 promotes diuresis and natriuresis by local production and action through ET(B) receptors in the renal medulla. In pathology, ET-1 mediates vasoconstriction, mesangial-cell proliferation, extracellular matrix production and inflammation, effects that are primarily conveyed by ET(A) receptors. Results obtained in animal models and in humans with the use of ERAs in CKD are encouraging; nevertheless, it is still under debate which receptor subtype should be targeted. According to most studies, selective inhibition of ET(A) receptors appears superior compared with nonselective ERAs because this approach does not interfere with the natriuretic, antihypertensive and ET clearance effects of ET(B) receptors. Although preliminary data in humans are promising, the potential role of ERAs in patients with CKD and the question of which receptor subtype should be targeted can only be clarified in randomized clinical trials.

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Section: Results From Animal Studiesmentioning

confidence: 98%

Section: Recent Evidence For Protective Effects Of Endothelin Receptomentioning

confidence: 99%

Endothelin receptor selectivity in chronic kidney disease: rationale and review of recent evidence

Neuhofer¹,

Pittrow

2009

Eur J Clin Investigation

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“…Blockade of NOS greatly enhanced ET-1-induced endothelial contraction, and both endothelial removal of oleuropein and NADPH oxidase inhibition attenuated the enhanced contraction [ 84 ]. ET-1 concentrations were observed to be increased in separate animal models of glaucoma [ 85 – 87 ], and this peptide plays a role in hypertension-related vascular injury [ 88 , 89 ]. NOX2 activity promotes ET-1 production in ECs [ 49 ], and NOX-mediated superoxide production contributes to ET-1-dependent regulation of vascular homeostasis in physiology and disease [ 90 ].…”

Section: Discussionmentioning

confidence: 99%

Pathological high intraocular pressure induces glial cell reactive proliferation contributing to neuroinflammation of the blood-retinal barrier via the NOX2/ET-1 axis-controlled ERK1/2 pathway

Shi,

Li,

Herb

et al. 2024

J Neuroinflammation

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Background NADPH oxidase (NOX), a primary source of endothelial reactive oxygen species (ROS), is considered a key event in disrupting the integrity of the blood-retinal barrier. Abnormalities in neurovascular-coupled immune signaling herald the loss of ganglion cells in glaucoma. Persistent microglia-driven inflammation and cellular innate immune system dysregulation often lead to deteriorating retinal degeneration. However, the crosstalk between NOX and the retinal immune environment remains unresolved. Here, we investigate the interaction between oxidative stress and neuroinflammation in glaucoma by genetic defects of NOX2 or its regulation via gp91ds-tat. Methods Ex vivo cultures of retinal explants from wildtype C57BL/6J and Nox2−/− mice were subjected to normal and high hydrostatic pressure (Pressure 60 mmHg) for 24 h. In vivo, high intraocular pressure (H-IOP) was induced in C57BL/6J mice for two weeks. Both Pressure 60 mmHg retinas and H-IOP mice were treated with either gp91ds-tat (a NOX2-specific inhibitor). Proteomic analysis was performed on control, H-IOP, and treatment with gp91ds-tat retinas to identify differentially expressed proteins (DEPs). The study also evaluated various glaucoma phenotypes, including IOP, retinal ganglion cell (RGC) functionality, and optic nerve (ON) degeneration. The superoxide (O2-) levels assay, blood-retinal barrier degradation, gliosis, neuroinflammation, enzyme-linked immunosorbent assay (ELISA), western blotting, and quantitative PCR were performed in this study. Results We found that NOX2-specific deletion or activity inhibition effectively attenuated retinal oxidative stress, immune dysregulation, the internal blood-retinal barrier (iBRB) injury, neurovascular unit (NVU) dysfunction, RGC loss, and ON axonal degeneration following H-IOP. Mechanistically, we unveiled for the first time that NOX2-dependent ROS-driven pro-inflammatory signaling, where NOX2/ROS induces endothelium-derived endothelin-1 (ET-1) overexpression, which activates the ERK1/2 signaling pathway and mediates the shift of microglia activation to a pro-inflammatory M1 phenotype, thereby triggering a neuroinflammatory outburst. Conclusions Collectively, we demonstrate for the first time that NOX2 deletion or gp91ds-tat inhibition attenuates iBRB injury and NVU dysfunction to rescue glaucomatous RGC loss and ON axon degeneration, which is associated with inhibition of the ET-1/ERK1/2-transduced shift of microglial cell activation toward a pro-inflammatory M1 phenotype, highlighting NOX2 as a potential target for novel neuroprotective therapies in glaucoma management.

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“…ET-1 levels are increased in some hypertension models 5,37 and this peptide plays a role in hypertension-associated vascular damage 38,39 . ET-1 regulates vascular tone not only by inducing vasoconstriction but also by modulating the response to other vasoactive agents; in addition, the proinflammatory properties of ET-1 seem to contribute to its hypertensinogenic effect 21,22,40 .…”

Section: Discussionmentioning

confidence: 99%

Pioglitazone Modulates the Vascular Contractility in Hypertension by Interference with ET-1 Pathway

Palacios

Hernanz

Martin

et al. 2019

Sci Rep

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Endothelin-1 (ET-1) is an important modulator of the vascular tone and a proinflammatory molecule that contributes to the vascular damage observed in hypertension. Peroxisome-proliferator activated receptors-γ (PPARγ) agonists show cardioprotective properties by decreasing inflammatory molecules such as COX-2 and reactive oxygen species (ROS), among others. We investigated the possible modulatory effect of PPARγ activation on the vascular effects of ET-1 in hypertension. In spontaneously hypertensive rats (SHR), but not in normotensive rats, ET-1 enhanced phenylephrine-induced contraction through ETA by a mechanism dependent on activation of TP receptors by COX-2-derived prostacyclin and reduction in NO bioavailability due to enhanced ROS production. In SHR, the PPARγ agonist pioglitazone (2.5 mg/Kg·day, 28 days) reduced the increased ETA levels and increased those of ETB. After pioglitazone treatment of SHR, ET-1 through ETB decreased ROS levels that resulted in increased NO bioavailability and diminished phenylephrine contraction. In vascular smooth muscle cells from SHR, ET-1 increased ROS production through AP-1 and NFκB activation, leading to enhanced COX-2 expression. These effects were blocked by pioglitazone. In summary, in hypertension, pioglitazone shifts the vascular ETA/ETB ratio, reduces ROS/COX-2 activation and increases NO availability; these changes explain the effect of ET-1 decreasing phenylephrine-induced contraction.

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The endothelin receptor antagonist ameliorates the hypertensive phenotypes of transgenic hypertensive mice with renin-angiotensin genes and discloses roles of organ specific activation of endothelin system in transgenic mice

Cited by 9 publications

References 43 publications

Endothelin receptor selectivity in chronic kidney disease: rationale and review of recent evidence

Endothelin receptor selectivity in chronic kidney disease: rationale and review of recent evidence

Pathological high intraocular pressure induces glial cell reactive proliferation contributing to neuroinflammation of the blood-retinal barrier via the NOX2/ET-1 axis-controlled ERK1/2 pathway

Pioglitazone Modulates the Vascular Contractility in Hypertension by Interference with ET-1 Pathway

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