Endothelin B receptor deficiency augments neuronal damage upon exposure to hypoxia–ischemia in vivo

Sirén, Anna‐Leena; Lewczuk, Piotr; Hasselblatt, Martin; Dembowski, Christoph; Schilling, Lothar; Ehrenreich, Hannelore

doi:10.1016/s0006-8993(02)02911-6

Cited by 28 publications

(22 citation statements)

References 32 publications

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“…Interestingly, ET-1 has been described as protecting astrocytes from hypoxic/ischemic injury in vitro (Ho et al, 2001). Accordingly, the absence of functional ET B receptors led to an augmented hypoxic/ischemic brain damage in vivo (Sirén et al, 2002). These protective effects of ET-1 might also involve modulation of the astrocytic gap junctional network.…”

Section: Discussionmentioning

confidence: 99%

Effect of endothelin‐1 on astrocytic protein content

Hasselblatt

Bunte

Dringen

et al. 2003

Glia

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The astrocytic endothelin (ET) receptors, ET(A) and ET(B), modulate calcium signaling and the astrocytic gap junctional network. The nonselective ET receptor ligand ET-1 inhibits gap junction permeability, an effect that can be blocked by tolbutamide. This mechanism may play a role in pathophysiological conditions such as ischemic stroke, characterized by elevated tissue ET-1 levels and hypertrophic-appearing reactive astrocytes. Therefore, the effect of ET-1 on cellular protein content was investigated in confluent once-passaged rat astrocyte cultures under serum-free conditions, by the Lowry method. Gap junction permeability was determined by the dye transfer technique. ET-1 prevented the decrease in astrocytic protein content observed in controls. The effect of ET-1 on cellular protein content was most pronounced in cultures seeded at high density, but it was attenuated in ET(B)-deficient (sl/sl) astrocytes. This effect could be blocked by the nonselective ET antagonist LU 302872 (10 micro M), as well as by the protein synthesis inhibitor cycloheximide (10 micro M). This increase in astrocytic protein content was inhibited by the ATP-sensitive K(+) channel blocker tolbutamide, which also antagonized the ET-1-induced reduction of gap junction permeability and reversed the morphological changes observed in astrocytes upon ET-1 treatment. Cytosine arabinoside (10 micro M), a DNA synthesis blocker, inhibited the ET-1-induced BrdU uptake without affecting the ET-1-induced increase in astrocytic protein content. To conclude, ET-1 induces an increase in astrocytic protein content as well as changes in astrocyte morphology in vitro. This hypertrophic response involves uncoupling of the astrocytic gap junctional network and is not dependent on DNA synthesis.

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Section: Discussionmentioning

confidence: 99%

Effect of endothelin‐1 on astrocytic protein content

Hasselblatt

Bunte

Dringen

et al. 2003

Glia

Self Cite

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“…Furthermore, ET Bselective agonists decreased apoptosis in rat endothelial cells (33) and ET B antagonists lead to increased apoptosis in rat and human endothelial cells (11,32). Cancer studies show that activation of the ET B receptor is considered a survival mechanism (24), whereas the inhibition or loss of the ET B receptor is protective against apoptosis in renal tubular cells of a mouse model of PKD (6) or neurons subjected to hypoxia-ischemia (35). It is clear from all these reports that the ET pathway is involved and that a better understanding of the mechanisms by which ET-1 leads to renal injury, especially renal apoptosis, is needed.…”

Section: Et-1 Pathway Apoptosis and Renal Injurymentioning

confidence: 99%

Endothelium-derived ET-1 and the development of renal injury

Miguel

Pollock

2015

American Journal of Physiology-Regulatory, Integrative and Comp

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De Miguel C, Pollock DM, Pollock JS. Endothelium-derived ET-1 and the development of renal injury. Am J Physiol Regul Integr Comp Physiol 309: R1071-R1073, 2015. First published May 20, 2015 doi:10.1152/ajpregu.00142.2015.-The role of the vasoactive peptide endothelin-1 (ET-1) in renal injury is not fully understood. In this review, we examine the genetic models available to understand the autocrine/paracrine mechanisms by which ET-1 leads to renal injury and propose the working hypothesis that endothelium-derived ET-1 induces renal injury by initiating renal tubular apoptosis in a paracrine manner.endothelin-1; apoptosis; renal injury ENDOTHELIN-1 (ET-1) is an endogenous 21 amino acid peptide that has powerful vasoactive properties. ET-1 is produced by many cell types including endothelial cells (40), cardiomyocytes (36), mesangial cells (31), and different segments of the nephron, especially collecting ducts (22). Increased activity of the ET-1 system has been described in several cardiovascular and renal diseases (25,28). ET-1 stimulates two G proteincoupled receptor subtypes, ET A and ET B receptors, with the same affinity for both receptors (7). Activation of each receptor subtype leads to different, and often opposite, physiological and pathophysiological results (3). Renal cortical and inner medullary tubules are rich in ET B receptors, whereas outer medullary tubules express both ET A and ET B receptors. Overactivation of the renal ET A pathway leads to hypertrophy, inflammation, and fibrosis. Actions of the ET B pathway promote clearance of ET-1 from circulation, stimulation of nitric oxide, and/or prostacyclin release, as well as increased sodium and water excretion (23). Several cell-type-specific endothelin pathway knockout mouse models and an ET B receptor-deficient rat model facilitate in-depth investigations into the activation of cellular source(s) and actions of ET-1. This review highlights the rationale for the use of genetic rodent models to elucidate the autocrine and/or paracrine mechanisms of ET-1-dependent development of renal apoptosis and injury. Based on the literature and our own preliminary findings, studying tunicamycin-induced renal apoptosis in two ET-1 genetic rodent models provides rationale for a working hypothesis that endothelium-derived ET-1 induces renal tubular apoptosis by a paracrine mechanism. ET-1 Pathway, Apoptosis, and Renal InjuryRenal injury is preceded by tubular apoptosis and loss of nephrons (26). Apoptotic cell death is characterized by a series of changes in cellular morphology, such as shrinkage of the cell membrane, condensation of nuclear chromatin, cellular fragmentation, and engulfment of the apoptotic bodies by neighboring cells (21). Different vasoactive peptides have been implicated in the regulation of cellular apoptosis; however, contradictory reports in the literature do not provide a clear role of ET-1 in apoptosis and renal injury. Some studies indicate that ET-1 attenuates apoptosis in vascular smooth muscle cells (39), endothelial cells (11), and...

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“…10,11 In addition, endothelins have been found to be involved in neuronal apoptosis in the central nervous system. 12,13 Recently, the roles of ET-1 in the pathogenesis of glaucoma have been clarified from different aspects.…”

Section: ϫ10mentioning

confidence: 99%

Endothelin-1 Enhances Glutamate-Induced Retinal Cell Death, Possibly through ET_AReceptors

Kobayashi

Oku

Fukuhara

et al. 2005

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.To determine the modification of the glutamate-induced death of retinal neurons by endothelin (ET)-1. METHODS. Cultured retinal neurons from fetal rats were exposed to glutamate (1.0 mM) alone or glutamate with ET-1 (10 Ϫ10-10 Ϫ7 M) for 10 minutes. Neuronal death was assessed by the trypan blue exclusion or TUNEL assays at 2, 6, and 24 hours after the exposure. The effects of adding BQ-123 or BQ-788, ET A , and ET B receptor antagonists, respectively, in combination with ET-1 was also assessed. RESULTS. Immunohistochemical analyses showed that the ETs as well as ET A and ET B receptors were expressed on cultured retinal neurons consisting mainly of amacrine cells. A brief exposure of the cultured retinal neurons to glutamate alone significantly increased the number of dead cells, and the addition of ET-1 with glutamate caused a further significant increase in retinal neuronal death compared with the cells exposed to glutamate alone. A significant increase in neuronal death was detected at doses of 10 nM of ET-1 and higher after a 24-hour exposure (P Ͻ 0.05, Dunnett), whereas brief exposure of neurons to up to 1 M ET-1 alone did not cause delayed cell death of neurons. BQ-123 (10 nM) suppressed the enhancement of retinal toxicity caused by ET-1 (10 nM), whereas BQ-788 had no significant effect. CONCLUSIONS. These results indicate that ET-1 enhances glutamate-induced retinal cell death, possibly through ET A receptors. ET-1 may act synergistically with glutamate to damage retinal neurons under hypoxic conditions. (Invest Ophthalmol Vis Sci. 2005;46:4684 -4690)

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Endothelin B receptor deficiency augments neuronal damage upon exposure to hypoxia–ischemia in vivo

Cited by 28 publications

References 32 publications

Effect of endothelin‐1 on astrocytic protein content

Effect of endothelin‐1 on astrocytic protein content

Endothelium-derived ET-1 and the development of renal injury

Endothelin-1 Enhances Glutamate-Induced Retinal Cell Death, Possibly through ET_AReceptors

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Endothelin B receptor deficiency augments neuronal damage upon exposure to hypoxia–ischemia in vivo

Cited by 28 publications

References 32 publications

Effect of endothelin‐1 on astrocytic protein content

Effect of endothelin‐1 on astrocytic protein content

Endothelium-derived ET-1 and the development of renal injury

Endothelin-1 Enhances Glutamate-Induced Retinal Cell Death, Possibly through ETAReceptors

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Endothelin-1 Enhances Glutamate-Induced Retinal Cell Death, Possibly through ET_AReceptors