Waardenburg syndrome (WS) is a clinically and genetically heterogeneous group of inherited disorders manifesting with sensorineural hearing loss and pigmentary anomalies. Here we present two Caucasian families with novel variants in EDNRB and SOX10 representing both sides of phenotype spectrum in WS. The c.521G>A variant in EDNRB identified in Family 1 leads to disruption of the cysteine disulfide bridge between extracellular segments of endothelin receptor type B and causes relatively mild phenotype of WS type II with low penetrance. The novel nonsense variant c.900C>A in SOX10 detected in Family 2 leads to PCWH syndrome and was found to be lethal.
We have demonstrated previously that activation of either the ETA or ETB receptor can induce acute electrographic seizures following the intrahippocampal infusion of endothelin-1 (ET-1) in immature (P12) rats. We also demonstrated that activation of the ETA receptor is associated with marked focal ischemia, while activation of the ETB receptor is not. Exploring the mechanisms underlying seizures induced by these two ET-1 receptor interactions can potentially provide insight into how focal ischemia in immature animals produces seizures and whether ischemiarelated seizures differ from seizures not associated with ischemia. To explore these seizure mechanisms we used microdialysis to determine biomarkers associated with seizures in P12 rats following the intrahippocampal infusion of two different agents: (1) ET-1, which activates both the ETA and ETB receptors and causes focal ischemia and (2) Ala-ET-1, which selectively activates only the ETB receptor and does not cause ischemia. Our results show that seizures associated with combined ETA and ETB receptor activation (and ischemia) have a different temporal distribution and microdialysis profile from seizures associated with ETB activation alone (and without ischemia). Seizures with combined activation peak within the first hour after infusion and the microdialysis profile is characterized by a significant increase in the ratio of glutamic acid to GABA. By contrast, seizures with activation of only the ETB receptor peak in the second hour after infusion and microdialysis shows a significant increase in the ratio of leukotriene B4 to prostaglandin E2. These findings suggest that ischemia-related seizures in immature animals involve an imbalance of excitation and inhibition, while non-ischemiarelated seizures involve an inflammatory process resulting from an excess of leukotrienes.
- MeSH
- endotelin-1 toxicita MeSH
- hipokampus účinky léků metabolismus MeSH
- ischemie mozku chemicky indukované metabolismus MeSH
- krysa rodu rattus MeSH
- potkani Wistar MeSH
- receptor endotelinu A metabolismus MeSH
- receptor endotelinu B metabolismus MeSH
- záchvaty chemicky indukované metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The endothelin axis (endothelins and their receptors) is strongly involved in physiological and pathological processes. ET-1 plays a crucial role in particular in tumor diseases. Endothelin-1 receptors (ET(A) and ET(B)) are deregulated and overexpressed in several tumors such as melanoma and glioma. We studied the binding of 24 monoclonal antibodies directed against human ET(B) receptors (hET(B)) to different melanoma cell lines. Few of these mAbs bound to all the melanoma cell lines. One of them, rendomab B49, bound to ET(B) receptors expressed at the surface of human glioma stem cells. More recently, we produced new antibodies directed against human ET(A) receptor (hET(A)). Several antibodies have been isolated and have been screened on different tumoral cells lines. As for the mAbs directed against the hET(B) receptor only some of new antibodies directed against ET(A) receptor are capable to bind the human tumoral cell lines. Rendomab A63 directed against hET(A) is one of them. We report the specificity and binding properties of these mAbs and consider their potential use in diagnosis by an in vivo imaging approach.
- MeSH
- antagonisté endotelinového receptoru A aplikace a dávkování metabolismus MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- endotelin-1 genetika metabolismus MeSH
- křečci praví MeSH
- lidé MeSH
- monoklonální protilátky aplikace a dávkování metabolismus MeSH
- myši nahé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- receptor endotelinu A genetika metabolismus MeSH
- receptor endotelinu B genetika metabolismus MeSH
- sekvence aminokyselin MeSH
- vazba proteinů fyziologie MeSH
- xenogenní modely - testy protinádorové aktivity metody MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide is an incretin hormone mimetic used in the treatment of diabetes. However, the effects of liraglutide on pulmonary hypertension (PH) and pulmonary endothelin (ET) system are unknown. Eight-week-old C57BL6/J mice were injected liraglutide or vehicle for 5 weeks. One week after injection, the mice were exposed to either room air (normoxia) or chronic hypoxia (10 % O(2)) for 4 weeks. The right ventricular systolic pressure (RVSP) was significantly higher in hypoxia + vehicle group than in normoxia + vehicle group. ET-1 mRNA expression in the lungs was comparable among all the groups. ET(B) mRNA and protein expression in the lungs was significantly lower in hypoxia + vehicle group than in normoxia + vehicle group. The above changes were normalized by liraglutide treatment. The expression of phospho-eNOS and phospho-AMPK proteins in the lungs was significantly higher in hypoxia + liraglutide group than in normoxia + vehicle group. We demonstrated for the first time that liraglutide effectively improved RVSP and RV hypertrophy in hypoxia-induced PH mice by activating eNOS through normalization of impaired ET(B) pathway and augmentation of AMPK pathway. Therefore, GLP-1R agonists can be promising therapeutic agents for PH.
- MeSH
- exprese genu MeSH
- hypoglykemika farmakologie terapeutické užití MeSH
- hypoxie farmakoterapie metabolismus MeSH
- liraglutid farmakologie terapeutické užití MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- plicní hypertenze farmakoterapie metabolismus MeSH
- receptor endotelinu B biosyntéza genetika MeSH
- receptor pro glukagonu podobný peptid 1 agonisté metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Renal medullary endothelin B receptors (ET(B)) mediate sodium excretion and blood pressure (BP) control. Several animal models of hypertension have impaired renal medullary ET(B) function. We found that 4-week high-caloric diet elevated systolic BP in Dahl salt-sensitive (Dahl S) rats (126+/-2 vs. 143+/-3 mm Hg, p<0.05). We hypothesized that renal medullary ET(B) function is dysfunctional in DS rats fed a high-caloric diet. We compared the diuretic and natriuretic response to intramedullary infusion of ET(B) agonist sarafotoxin 6c (S6c) in DS rats fed either a normal or high-caloric diet for 4 weeks. Urine was collected during intramedullary infusion of saline for baseline collection followed by intramedullary infusion of either saline or S6c. We first examined the ET(B) function in DS rats fed a normal diet. S6c increased urine flow (2.7+/-0.3 microl/min during baseline vs. 5.1+/-0.6 microl/min after S6c; p<0.05; n=5) and sodium excretion (0.28+/-0.05 vs. 0.81+/-0.17 micromol/min; p<0.05), suggesting that DS rats have renal medullary ET(B) function. However, DS rats fed a high-caloric diet displayed a significant increase in urine flow (2.7+/-0.4 vs. 4.2+/-0.4 microl/min, baseline vs. S6c infusion, respectively; p<0.05, n=6), but no significant change in sodium excretion in response to S6c (0.32+/-0.06 vs. 0.45+/-0.10 micromol/min). These data demonstrate that renal medullary ET(B) function is impaired in DS rats fed a high-caloric diet, which may be contributed to the elevation of blood pressure during high-caloric feeding in this model.
- MeSH
- dieta s vysokým obsahem tuků škodlivé účinky MeSH
- dřeň ledvin účinky léků metabolismus MeSH
- hypertenze etiologie metabolismus MeSH
- krevní tlak účinky léků fyziologie MeSH
- krysa rodu rattus MeSH
- peptidy farmakologie MeSH
- potkani inbrední Dahl MeSH
- přijímání potravy účinky léků fyziologie MeSH
- receptor endotelinu B agonisté metabolismus MeSH
- signální transdukce účinky léků fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
We examined the upregulation of ET-1/ETBR/eNOS signaling in renoprotective effect of vitamin D in kidney fibrosis model in mice using unilateral ureteral obstruction (UUO). One group was treated with intraperitoneal injection of 0.125 mg/kg of Calcitriol (UUO+VD). Vascular remodeling was quantified based on lumen area and lumen/wall area ratio (LWAR) of intrarenal arteries using Sirius Red staining. ET-1, ETBR, eNOS, CD31 and VEGF mRNA expressions were quantified using qRT-PCR. Focusing on endothelin-1 (ET-1) signaling in endothelial cells (EC), siRNA of ET-1 was performed in human umbilical vein endothelial cells (HUVEC) for reducing ET-1 expression. Then HUVECs were treated with and without 100 nM Calcitriol treatment in hypoxic and normoxic conditions to elucidate ET-1/eNOS signaling. Our in vivo study revealed vascular remodeling and renal ischemia attenuation after Calcitriol treatment. Vascular remodeling was attenuated in the UUO+VD group as shown by increasing lumen areas and LWAR in intrarenal arteries. These findings were associated with significant higher CD31 and VEGF mRNA expression compared to the UUO group. Vitamin D treatment also increased ET-1, ETBR and eNOS mRNA expressions. Our in vitro study demonstrated Calcitriol induced ET-1 and eNOS mRNA expressions upregulation in HUVEC under normoxic and hypoxic condition. Meanwhile, siRNA for ET-1 inhibited the upregulation of eNOS mRNA expression after Calcitriol treatment. Vitamin D ameliorates kidney fibrosis through attenuating vascular remodeling and ischemia with upregulating ET-1/ETBR and eNOS expression.
- MeSH
- endoteliální buňky pupečníkové žíly (lidské) MeSH
- endotelin-1 biosyntéza MeSH
- fibróza MeSH
- ischemie farmakoterapie metabolismus MeSH
- lidé MeSH
- messenger RNA biosyntéza MeSH
- myši MeSH
- nemoci ledvin farmakoterapie metabolismus MeSH
- receptor endotelinu B biosyntéza MeSH
- remodelace cév účinky léků fyziologie MeSH
- synthasa oxidu dusnatého, typ III biosyntéza MeSH
- upregulace účinky léků fyziologie MeSH
- vitamin D farmakologie terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The endothelin (ET) and prorenin/renin/prorenin receptor (PRR) systems have opposing physiological effects on collecting duct (CD) salt and water reabsorption. It is unknown if the CD ET and renin/PRR systems interact, hence we examined the effects of deleting CD renin or nephron PRR on CD ET system components. PRR knockout (KO) mice were polyuric and had markedly increased urinary ET-1 and inner medullary CD (IMCD) ET-1 mRNA. PRR KO mice had greatly increased IMCD ETA receptor mRNA and protein, while ETB mRNA and protein were decreased. Water loaded wild-type mice with similar polyuria as PRR KO mice had modestly increased urinary ET-1 excretion and inner medullary ET-1 mRNA, while inner medullary ETA and ETB mRNA or protein expression were unaffected. In contrast to PRR KO, CD prorenin/renin KO did not alter ET system components. Taken together, these results suggest that the nephron PRR is involved in regulating CD ET system expression, but this effect may be independent of CD-derived renin.
- MeSH
- dřeň ledvin metabolismus MeSH
- endotelin-1 biosyntéza genetika MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- nefrony metabolismus MeSH
- receptor endotelinu A biosyntéza genetika MeSH
- receptor endotelinu B biosyntéza genetika MeSH
- receptory buněčného povrchu nedostatek MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Endothelin B (ET(B)) receptors present in abundance the central nervous system (CNS) have been shown to have significant implications in its development and neurogenesis. We have targeted ET(B) receptors stimulation using a highly specific agonist, IRL-1620, to treat CNS disorders. In a rat model of cerebral ischemia intravenous administration IRL-1620 significantly reduced infarct volume and improved neurological and motor functions compared to control. This improvement, in part, is due to an increase in neuroregeneration. We also investigated the role of IRL-1620 in animal models of Alzheimer's disease (AD). IRL-1620 improved learning and memory, reduced oxidative stress and increased VEGF and NGF in Abeta treated rats. IRL-1620 also improved learning and memory in an aged APP/PS1 transgenic mouse model of AD. These promising findings prompted us to initiate human studies. Successful chemistry, manufacturing and control along with mice, rat and dog toxicological studies led to completion of a human Phase I study in healthy volunteers. We found that a dose of 0.6 microg/kg of IRL-1620 can be safely administered, three times every four hours, without any adverse effect. A Phase II clinical study with IRL-1620 has been initiated in patients with cerebral ischemia and mild to moderate AD.
- MeSH
- endoteliny farmakologie terapeutické užití MeSH
- klinické zkoušky jako téma metody MeSH
- lidé MeSH
- nemoci centrálního nervového systému farmakoterapie metabolismus MeSH
- neurodegenerativní nemoci farmakoterapie metabolismus MeSH
- oxidační stres účinky léků fyziologie MeSH
- peptidové fragmenty farmakologie terapeutické užití MeSH
- preklinické hodnocení léčiv metody MeSH
- receptor endotelinu B agonisté metabolismus MeSH
- regenerace nervu účinky léků fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The global epidemic of diabetes is of significant concern. Diabetes associated vascular disease signifies the principal cause of morbidity and mortality in diabetic patients. It is also the most rapidly increasing risk factor for cognitive impairment, a silent disease that causes loss of creativity, productivity, and quality of life. Small vessel disease in the cerebral vasculature plays a major role in the pathogenesis of cognitive impairment in diabetes. Endothelin system, including endothelin-1 (ET-1) and the receptors (ET(A) and ET(B)), is a likely candidate that may be involved in many aspects of the diabetes cerebrovascular disease. In this review, we took a brain-centric approach and discussed the role of the ET system in cerebrovascular and cognitive dysfunction in diabetes.
- MeSH
- antagonisté endotelinového receptoru A aplikace a dávkování metabolismus MeSH
- antagonisté endotelinového receptoru B aplikace a dávkování metabolismus MeSH
- endoteliny agonisté antagonisté a inhibitory metabolismus MeSH
- komplikace diabetu farmakoterapie metabolismus MeSH
- lidé MeSH
- mozek účinky léků metabolismus MeSH
- mozkový krevní oběh účinky léků fyziologie MeSH
- receptor endotelinu A metabolismus MeSH
- receptor endotelinu B metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: Early addition of endothelin (ET) type A (ETA) receptor blockade to complex renin-angiotensin system (RAS) blockade has previously been shown to provide better renoprotection against progression of chronic kidney disease (CKD) in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX). In this study, we examined if additional protection is provided when ETA blockade is applied in rats with already developed CKD. METHODS: For complex RAS inhibition, an angiotensin-converting enzyme inhibitor along with angiotensin II type 1 receptor blocker was used. Alternatively, ETA receptor blocker was added to the RAS blockade. The treatments were initiated 6 weeks after 5/6 NX and the follow-up period was 50 weeks. RESULTS: When applied in established CKD, addition of ETA receptor blockade to the complex RAS blockade brought no further improvement of the survival rate (30% in both groups); surprisingly, aggravated albuminuria (588 ± 47 vs. 245 ± 38 mg/24 h, p < 0.05) did not reduce renal glomerular injury index (1.25 ± 0.29 vs. 1.44 ± 0.26), did not prevent the decrease in creatinine clearance (203 ± 21 vs. 253 ± 17 μl/min/100 g body weight), and did not attenuate cardiac hypertrophy to a greater extent than observed in 5/6 NX TGR treated with complex RAS blockade alone. CONCLUSIONS: When applied in the advanced phase of CKD, addition of ETA receptor blockade to the complex RAS blockade brings no further beneficial renoprotective effects on the CKD progression in 5/6 NX TGR, in addition to those seen with RAS blockade alone.
- MeSH
- albuminurie MeSH
- angiotensiny účinky léků metabolismus MeSH
- antagonisté endotelinového receptoru A farmakologie MeSH
- blokátory receptorů AT1 pro angiotensin II farmakologie MeSH
- chronická renální insuficience metabolismus MeSH
- hodnoty glomerulární filtrace účinky léků MeSH
- hypertenze MeSH
- indoly farmakologie MeSH
- inhibitory ACE farmakologie MeSH
- kardiomegalie MeSH
- kombinovaná farmakoterapie MeSH
- kreatinin metabolismus MeSH
- krevní tlak účinky léků MeSH
- krysa rodu rattus MeSH
- ledviny účinky léků metabolismus MeSH
- losartan farmakologie MeSH
- míra přežití MeSH
- nefrektomie MeSH
- potkani Sprague-Dawley MeSH
- potkani transgenní MeSH
- progrese nemoci MeSH
- pyrrolidiny farmakologie MeSH
- receptor endotelinu A účinky léků metabolismus MeSH
- receptor endotelinu B účinky léků metabolismus MeSH
- renin-angiotensin systém účinky léků MeSH
- renin účinky léků metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH