Abstract P016: Sex Differential Effects Of Hyperoxia And Thioredoxin Reductase-1 Inhibition On The Kidney Endothelin-1 System

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Carmen De Miguel ◽  
Aleena George ◽  
Sara N Biswal ◽  
Abigayle Kraus ◽  
Katelyn Dunigan ◽  
...  
Keyword(s):  
Thioredoxin Reductase ◽  
Kidney Injury ◽  
Fold Increase ◽  
Receptor Expression ◽  
Diabetes Research ◽  
Endothelin 1 ◽  
Thioredoxin Reductase 1 ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Glomerular Morphology

The vasoactive peptide endothelin-1 (ET-1) is critical in lung and kidney injury. Notably, renal damageand hyperoxia-induced lung disease are more prevalent in males than females. Aurothioglucose (ATG),an inhibitor of thioredoxin reductase-1, attenuates hyperoxia-induced lung injury in mice; however, theeffects of hyperoxia and/or ATG treatment on the kidney ET-1 system remain unknown. Wehypothesized that hyperoxia would activate the renal ET-1 system and that ATG treatment wouldattenuate this activation. Male and female adult C57Bl/6 mice received a single injection of saline orATG (25mg/Kg, i.p.) and were exposed to room air (RA) or >90% O2 for 72 hours. Kidney and spleen werecollected for assessment of the ET-1 system by RT-PCR and glomerular morphology and immune cellinfiltration were evaluated by histology and immunohistochemistry, respectively. In male mice,hyperoxia reduced the cortical expression of ET-1 (RA vs. hyperoxia: 1 ± 0.05 vs. 0.34 ± 0.04, p<0.05;n=3-4/group) and ameliorated the expression of ETA receptor. In RA males, treatment with ATGsignificantly halved the expression of ET-1 and ETB receptor (saline vs. ATG, ET-1: 1 ± 0.05 vs. 0.45 ± 0.07,p<0.05; n=3-4/group; ETB receptor: 1 ± 0.09 vs. 0.37 ± 0.10, p<0.05; n=3-4/group), but had no effect inhyperoxic males. Contrarily, hyperoxic females demonstrated a 3-fold upregulation of corticalETB receptor expression, which was significantly prevented by ATG (saline vs. ATG: 2.80 ± 0.37 vs. 0.95 ±0.27, p<0.05; n=3-4/group). ATG treatment in hyperoxic females also decreased the cortical expressionof ET-1 and ETA receptor. No changes in cortical inflammation or glomerular morphology were observed.Further preliminary results showed that hyperoxia led to a 4-fold increase in splenic ET-1 expression insaline-treated mice, and a 7-fold increase in mice treated with ATG. These results demonstrate sexdifferences in the effects of hyperoxia and ATG treatment in the renal ET-1 system and highlight ATG asa possible therapeutic target to attenuate hyperoxia-induced kidney damage. Funded by NIHK01HL145324 and UAB Diabetes Research Center Pilot Project grant to CDM.

scholarly journals Regulation of the Endothelin/Endothelin Receptor System by Interleukin-1β in Human Myometrial Cells

Endocrinology ◽  
2005 ◽  
Vol 146 (11) ◽  
pp. 4878-4886 ◽  
Author(s):  
Michelle Breuiller-Fouché ◽  
Catherine Morinière ◽  
Emmanuelle Dallot ◽  
Stéphanie Oger ◽  
Régis Rebourcet ◽  
...  
Keyword(s):  
Prolonged Exposure ◽  
Receptor Expression ◽  
Receptor Subtype ◽  
Mrna Levels ◽  
Receptor System ◽  
Myometrial Cell ◽  
Myometrial Cells ◽  
Uterine Contractions ◽  
Eta Receptor ◽  
Etb Receptor

Proinflammatory cytokines produced at the fetomaternal interface, such as IL-1β, have been implicated in preterm and term labor. The present study was performed to evaluate the influence of IL-1β on the endothelin (ET)/ET receptor system in human myometrial cells. We report that myometrial cells under basal conditions not only respond to but also secrete ET-1, one of the main regulators of uterine contractions. Prolonged exposure of the cells to IL-1β led to a decrease in prepro-ET-1 and ET-3 mRNA correlated with a decrease in immunoreactive ET-1 and ET-3 levels in the culture medium. Whereas ETA receptor expression at both protein and mRNA levels was not affected by IL-1β treatment, we demonstrated an unexpected predominance of the ETB receptor subtype under this inflammatory condition. Whereas the physiological function of ETB remains unclear, we confirmed that only ETA receptors mediate ET-1-induced myometrial cell contractions under basal conditions. By contrast, prolonged exposure of the cells to IL-1β abolished the contractile effect induced by ET-1. Such a regulation of IL-1β on the ET release and the balance of ETA to ETB receptors leading to a loss of ET-1-induced myometrial cell contractions suggest that complex regulatory mechanisms take place to constraint the onset of infection-induced premature contractions.

Analysis of vasocontractile responses to endothelin-1 in rabbit retinal vessels using an ETA receptor antagonist and an ETB receptor agonist

Life Sciences ◽  
1993 ◽  
Vol 53 (6) ◽  
pp. PL111-PL115 ◽  
Author(s):  
Kazuo Takei ◽  
Tsuyoshi Sato ◽  
Tomohito Nonoyama ◽  
Takashi Miyauchi ◽  
Katsutoshi Goto
Keyword(s):  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Retinal Vessels ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Eta Receptor Antagonist

Differential regulation of renal regional blood flow by endothelin-1

1996 ◽  
Vol 271 (6) ◽  
pp. F1166-F1172 ◽  
Author(s):  
K. Gurbanov ◽  
I. Rubinstein ◽  
A. Hoffman ◽  
Z. Abassi ◽  
O. S. Better ◽  
...  
Keyword(s):  
Blood Flow ◽  
Receptor Antagonist ◽  
Bolus Injection ◽  
Regional Blood Flow ◽  
Doppler Flowmetry ◽  
Endothelin 1 ◽  
Male Wistar Rats ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Eta Receptor Antagonist

The present study evaluated the effects and mechanisms of action of endothelin-1 (ET-1) on medullary and cortical blood flow (MBF and CBF, respectively). CBF and MBF were measured simultaneously by laser-Doppler flowmetry in anesthetized male Wistar rats. Bolus injection of ET-1 (1.0 nmol/kg iv) produced a sustained decrease in CBF (delta = -30%) and a transient increase in MBF (delta = +35%). The medullary vasodilation induced by ET-1 was observed with doses lower than that required to produce cortical vasoconstriction; was completely blocked by bosentan, a mixed ETA/B-receptor antagonist; and was mimicked by IRL-1620, a specific ETB-receptor agonist. In contrast, BQ-123, an ETA-receptor antagonist, failed to inhibit the ET-1-dependent medullary vasodilation but effectively blocked the cortical vasoconstriction induced by the peptide. Finally, inhibition of nitric oxide (NO) synthase completely abolished, whereas cylooxygenase inhibition attenuated, the effect of ET-1 on MBF. The data demonstrate that ET-1 exerts opposite effects on renal cortical and medullary circulation, i.e., ETA-receptor-mediated cortical vasoconstriction and ETB-mediated medullary vasodilation. Furthermore, the medullary vasodilation induced by ET-1 is dependent on the NO system and, to a lesser extent, on prostaglandin generation.

scholarly journals Role of the Endothelin-1 System in the Luteolytic Process of Pseudopregnant Rabbits

Endocrinology ◽  
2005 ◽  
Vol 146 (3) ◽  
pp. 1293-1300 ◽  
Author(s):  
Cristiano Boiti ◽  
Gabriella Guelfi ◽  
Gabriele Brecchia ◽  
Cecilia Dall’Aglio ◽  
Piero Ceccarelli ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Prostaglandin F2α ◽  
Receptor Protein ◽  
Corpora Lutea ◽  
Positive Staining ◽  
Endothelin 1 ◽  
Cox Inhibitor ◽  
Eta Receptor ◽  
Etb Receptor

The aim of this study was to better understand the role of the endothelin-1 (ET-1) system in the process of controlling the corpora lutea (CL) life span in rabbits. ET-1 (10 μg iv) administration at d 9 and 12 of pseudopregnancy induced a functional luteolysis within 24 h of injection, but it was ineffective at both d 4 and 6. Pretreatments with Bosentan, a dual ETA/ETB receptor antagonist, or cyclooxygenase (COX) inhibitor blocked the luteolytic action of ET-1 but not that induced by prostaglandin F2α (PGF2α). In CL cultured in vitro, ET-1 increased (P ≤ 0.01) both PGF2α production and luteal nitric oxide synthase activity but decreased (P ≤ 0.01) progesterone release. Addition of ETA receptor antagonist BQ123 or COX inhibitor blocked the ET-1 luteolytic effects. Positive staining for ET-1 receptors was localized in ovarian blood vessels, granulosa cells of large follicles, and luteal cells. Immunoblot analysis of ET-1 receptor protein revealed a strong band of approximately 48 kDa in d-9 CL. Up to d 6 of pseudopregnancy, ET-1 mRNA abundance in CL was poorly expressed but then increased (P ≤ 0.01) at d 9 and 13. ETA-receptor transcript increased (P ≤ 0.01) at d 6, remained at the same level up to d 13, and then declined to the lowest (P ≤ 0.01) levels at d 22. ETB-receptor mRNA increased (P ≤ 0.01) throughout the late-luteal stage from d 13 up to d 18. Our data suggest that the luteolytic action of ET-1 may be a result of PGF2α synthesis from both luteal and accessory cells, via the COX pathways.

scholarly journals Autocrine effects of endothelin-1 on leukocyte-endothelial interaction: stimulation of endothelin B receptor subtype reduces endothelial adhesiveness via a nitric oxide-dependent mechanism

Blood ◽  
1996 ◽  
Vol 88 (10) ◽  
pp. 3894-3900 ◽  
Author(s):  
T Murohara ◽  
AM Lefer
Keyword(s):  
Nitric Oxide ◽  
Receptor Antagonist ◽  
Receptor Subtype ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Endothelin B ◽  
Eta Receptor Antagonist ◽  
Inhibition Of Thrombin

The effects of endothelin-1 (ET-1) on P-selectin-mediated leukocyte endothelial interaction were examined in vitro. Adherence of autologous polymorphonuclear leukocytes (PMNs) to the endothelium was markedly enhanced by endothelial stimulation with either (2 U/mL) thrombin, (1 mumol/L) histamine, or (100 nmol/L) phorbol myristate acetate (PMA). In contrast, ET-1 alone (10 and 100 nmol/L) only slightly increased the number of adhering PMNs. The increased PMN adherence to thrombin- or histamine-stimulated endothelium, which was blocked by an anti-P-selectin monoclonal antibody, was also significantly attenuated by preincubation of coronary segments with (100 nmol/L) ET-1. We further investigated the mechanism of this anti-adherence action of ET-1 on thrombin-stimulated endothelial adhesiveness. Preincubation of coronary segments with a selective ETA receptor antagonist, BQ485 (1 mumol/L), had no effect on ET-1 inhibition of thrombin-induced PMN adherence. In contrast, preincubation with a selective ETB receptor antagonist, BQ788 (1 mumol/L) significantly reversed ET-1 inhibition of thrombin-induced PMN adherence, whereas the selective ETB receptor agonist BQ-3020 mimicked the inhibitory action of ET-1 on thrombin-induced PMN adherence. Furthermore, (100 mumol/L) N omega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, significantly attenuated ET-1 inhibition of thrombin-stimulated PMN adherence. These results suggest that ET-1 may inhibit P-selectin-mediated leukocyte-endothelial interaction via ETB receptor stimulation and subsequent endothelial NO formation. This autocrine effect of ET-1 may be involved in pathophysiologic states such as early atherogenesis by preventing leukocyte-endothelial interaction in constricted blood vessels.

Endothelin-1 induces mucosal mast cell degranulation and tissue injury via ETA receptors

2002 ◽  
Vol 103 (s2002) ◽  
pp. 31S-34S ◽  
Author(s):  
Mihály BOROS ◽  
László SZALAY ◽  
József KASZAKI
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Receptor Antagonist ◽  
Mast Cell Degranulation ◽  
Tissue Response ◽  
Mucosal Mast Cell ◽  
Receptor Antagonists ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Etb Receptor

The effects of endothelin-1 (ET-1) on mucosal mast cells are of special interest, since they may be an important component of the tissue response that occurs during ischaemic preconditioning or ischaemia/re-oxygenation injuries. Increasing doses of ET-1 were administered intravenously to anaesthetized rats. In a second series of experiments, animals were pretreated with the ETA receptor antagonists BQ-610 or ETR-P1/fl peptide, or with the ETB receptor antagonist IRL-1038. Intestinal perfusion changes were recorded, and the proportion of degranulated mast cells and the degree of mucosal damage were determined in ileal biopsies. ET-1 induced dose-dependent alterations in the haemodynamic and morphological parameters, and caused significant mast cell degranulation. These changes were inhibited significantly by pretreatment with the ETA receptor antagonists, but not with the ETB receptor antagonist. We conclude that a cross-talk exists between endothelial cell-derived humoral mediators and the intestinal mast cell system.

Function and survival of dendritic cells depend on endothelin-1 and endothelin receptor autocrine loops

Blood ◽  
2004 ◽  
Vol 104 (7) ◽  
pp. 2107-2115 ◽  
Author(s):  
Georgi Guruli ◽  
Beth R. Pflug ◽  
Stefana Pecher ◽  
Valeria Makarenkova ◽  
Michael R. Shurin ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Endothelin Receptors ◽  
Interleukin 12 ◽  
Endothelin 1 ◽  
Selective Blockade ◽  
Biologic Effects ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Major Antigen ◽  
And Function

Abstract The biologic effects of endothelin-1 (ET-1) are not limited to its potent vasoconstricting activity. The endothelin receptors, ETA and ETB, have differential tissue and functional distributions. Here we showed that dendritic cells (DCs), the major antigen-presenting cells in the adaptive limb of the immune system, produce large amounts of ET-1 and significantly increase the expression of endothelin receptors upon maturation. Selective blockade of the ETA receptor significantly reduced expression of the mature DC marker CD83, decreased the production of the immunostimulatory cytokine interleukin-12, down-regulated DC ability to stimulate T cells, and promoted DC apoptosis. Selective ETB receptor blockade, on the other hand, resulted in increased expression of CD83 and improved DC survival. Therefore, ET-1/ETA/ETB autocrine/paracrine loops on DCs appear to be essential for the normal maturation and function of human DCs, presenting a unique target for immunomodulatory therapies. (Blood. 2004;104:2107-2115)

Interaction among ET-1, endothelium-derived nitric oxide, and prostacyclin in pulmonary arteries and veins

1994 ◽  
Vol 267 (1) ◽  
pp. H139-H147 ◽  
Author(s):  
T. M. Zellers ◽  
J. McCormick ◽  
Y. Wu
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Veins ◽  
Pulmonary Arteries ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Potent Vasoconstrictor ◽  
Eta Receptor Antagonist ◽  
Arteries And Veins

Endothelin-1 causes vasodilation of the intact porcine pulmonary vascular bed. To determine the cause of this vasodilation, we investigated the interactions of endothelin-1 (ET-1), endothelium-derived nitric oxide (EDNO), and prostacyclin in isolated small porcine pulmonary arteries and veins under in vitro conditions. ET-1 caused concentration-dependent contractions in arteries and veins, augmented by the nitric oxide synthase (NOS) inhibitor, N omega-nitro-L-arginine, in pulmonary veins. BQ-123 (ETA-receptor antagonist) depressed the ET-1-induced contractions. Sarafotoxin S6C, an ETB-receptor agonist, caused contractions of pulmonary veins only. Endothelium-dependent relaxations to bradykinin and ET-1 were greater in pulmonary veins compared with arteries, inhibited by N omega-nitro-L-arginine, and reversed by L-arginine. BQ-123 augmented ET-1-induced arterial relaxation. ET-3 and sarafotoxin S6C, ETB-receptor agonists, caused comparable endothelium-dependent relaxations in arteries and veins. ET-1 caused a fourfold greater increase in prostacyclin release in pulmonary veins compared with arteries. We conclude that ET-1 is a potent vasoconstrictor of porcine pulmonary vessels and stimulates the release of EDNO and prostacyclin, which oppose the contractions to the peptide. The release of these endothelium-derived vasodilators appears greater in pulmonary veins.

Gender Differences In Renal Blood Flow In Response To Endothelin-1 In a Mouse Model Of Sickle Cell Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1012-1012
Author(s):  
J Brett Heimlich ◽  
Matthew J McGhee ◽  
Steffen E. Meiler ◽  
Abdullah Kutlar ◽  
David M Pollock
Keyword(s):  
Gender Differences ◽  
Blood Flow ◽  
Mrna Expression ◽  
Sickle Cell ◽  
Cell Disease ◽  
Male And Female ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Males And Females

Abstract There is increasing evidence that Endothelin-1 (ET-1) plays a significant role in the pathogenesis of complications of sickle cell disease (SCD. SCD patients have elevated levels of endothelin-1 both in plasma and urine and ET-1 has been implicated in SCN, pain modulation, vaso-occlusive episodes, and acute chest syndrome. In the kidney, ET-1 is a potent vasoconstrictor, anti-natriuretic, and hypertrophic factor when signaling through the ETA receptor. ET-1 is released in response to shear stress, hypoxia, thrombin activation, and inflammatory cytokines, all of which are prevalent in SCD. Gender differences exist in other disease models, in which ET-1 plays a contributory pathophysiological role, with males typically exhibiting increased ET-1 mRNA expression, exaggerated ETA-mediated effects, and higher levels of renal injury. Little research exists highlighting the differences between males and females in SCD. It has been observed that the level of Hb F, a major modifier of disease severity in SCD, is higher in females compared to males. In addition, one study examined responses to chronic transfusion therapy, finding males to have increased vascular resistance and resulting decrease in oxygen delivery in response to transfusion when compared to females. We hypothesized that male SCD mice have enhanced ETA mediated responses to ET-1, ultimately leading to renal injury. To test this, we used male and female ‘HbS only’ knock in SCD mice to measure renal artery blood flow velocity (BFV) via laser Doppler flowmetry in response to an ET-1 bolus (1nm/kg in 100uL saline). Male mice had an exaggerated decrease in BFV relative to females at 1, 5, and 10 minutes post ET-1 infusion while renal artery diameter remained unchanged throughout the experiment (84.4±5.8 vs. 56±5.7% of BFV baseline at 10 minutes, p<0.05, n=6). A follow up experiment was performed to determine ET-1, ETA receptor, and ETB receptor mRNA expression in the cortex of male and female SCD mice via qPCR. Males and females surprisingly exhibited no significant difference in these parameters although there was a strong trend suggesting females have increased levels of ET-1 mRNA expression compared to males (1.62±0.51 fold increase vs. males, p=0.056, n=5-6). While the exaggerated sensitivity to an ET-1 bolus is partially explained by the relative decrease in ET-1 mRNA expression in males, we nevertheless expected to see differences in ETA/ETB receptor expression. However, receptor-ligand binding could perhaps offer an alternate explanation for this phenomenon. Sex hormones are heavily implicated in other sex differences studies and the potential protective role of estrogen and/or detrimental role for testosterone are both viable explanations for the dichotomy seen in SCD. These data demonstrate a novel sexual dimorphism for SCD, revealing new insights into sex-specific pathophysiology that could have broad effects on treatment strategies in sickle cell nephropathy. Disclosures: No relevant conflicts of interest to declare.

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